Heterocycle-condensed morphinoid derivatives (II)

ABSTRACT

Heterocycle-condensed morphinoid derivatives of formula (I), or solvates or salts thereof,                    
     are potent and selective delta opioid agonists and antagonists and are useful as i.a. analgesics. Pharmaceutical compositions containing such compounds, the use of such compounds as therapeutic agents, a method of treatment comprising the administration of such compounds, and a process for the preparation of such compounds are also described.

The present invention is concerned with novel morphinoid compounds,processes for their preparation and their use in medicine.

The presence of at least three populations of opioid receptors (mu,delta and kappa) is now well established and documented and all threeappear to be present in the central and peripheral nervous system ofmany species including man (Lord J. A. H. et al., Nature 1977, 267,495).

Activation of all three opioid receptor subtypes can lead toantinociception in animal models. In particular, studies with peptidicdelta agonists have indicated that activation of the delta receptorproduces antinociception in rodents, primates and can induce clinicalanalgesia in man (D. E. Moulin et al. Pain, 1985, 23, 213). Evidenceexists that suggest a lesser propensity of delta agonists to cause theusual side-effects associated with mu and kappa activation (Galligan etal, J. Pharm. Exp. Ther., 1984, 229, 641).

U.S. Pat. Nos. 5,223,507 and 5,225,417 (G. D. Searle & Co.) disclosebicycle-condensed morphinoid compounds which are said to be delta opioidagonists having therapeutic utility as analgesics agents.

WO 94/07896 (Toray Ind. Inc.) discloses indole-condensed morphinoidcompounds useful as immunosuppressants, anti-allergic andanti-inflammatory agents.

We have now discovered a novel class of substitutedmonoheterocycle-condensed morphinoid derivatives which are potent andselective delta opioid agonists and antagonists which may therefore beof potential therapeutic utility as analgesics, immunosuppressants toprevent rejection in organ transplant and skin graft, anti-allergic andanti-inflammatory agents, brain cell protectant, agents for treatingdrug and alcohol abuse, gastritis, diarrhoea, cardiovascular andrespiratory diseases, cough, mental illness and epilepsy and, ingeneral, for the treatment of those pathological conditions whichcustomarily can be treated with agonists and antagonists of the deltaopioid receptor.

According to the present invention, there is provided a compound, or asolvate or salt thereof of formula (I):

in which,

R₁ is hydrogen, linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆cycloalkylalkyl, each of the latter three groups being optionallysubstituted by a hydroxy group when C_(≧2), C₃₋₅ alkenyl, aryl, aralkylor furan-2 or 3-yl alkyl or (CH₂)_(m)COR wherein m is 0 to 5 and Rrepresents linear or branched C₁₋₆ alkyl, hydroxy, C₁₋₅ alkoxy, OC₃₋₆alkenyl or alkylaryl, NR₁₀R₁₁ where R₁₀ and R₁₁ may be the same ordifferent, and each is hydrogen, linear or branched C₁₋₆ alkyl, C₄₋₆cycloalkylalkyl, C₃₋₅ alkenyl, aryl or aralkyl; or R₁ is a group A-Bwherein A represents C₁₋₁₀ alkylene and B represents substituted orunsubstituted aryl or heteroaryl;

R₂ is hydrogen, hydroxy or C₁₋₅ alkoxy, preferably methoxy, halogen,nitro, NR₁₀R₁₁, SR₁₀, where R₁₀ and R₁₁ have the same meaning describedabove and in addition R₁₀ is COR₁, preferably acetyl;

R₃ is hydrogen, linear or branched C₁₋₆ alkyl, preferably ethyl,hydroxy, C₁₋₅ alkoxy, preferably methoxy, halogen, preferably bromine,or (CH₂)_(m)COR where m and R have the same meaning described above,SR₁₀, nitro, NR₁₀R₁₁, NHCOR₁₀, NHSO₂R₁₀, where R₁₀ and R₁₁, have thesame meaning described above, preferably hydrogen or methyl;

R₄ and R₅, which may be the same or different, are each independentlyhydrogen, hydroxy, C₁₋₅ alkoxy, preferably methoxy, O-phenyl or togethermay form an oxy group (—O—); or R₄ together with R₃ may form amethylendioxy group (—OCH2O—); R₆ is a group

 or a five- or six-membered heteroaromatic group, containing up to threeheteroatoms such as O, S and N, substituted with R₃ in which R₃ has thesame meaning described above, there being up to three R₃ groups in thering,

or R₆ is a group C(Z)R₁₂, in which Z is oxygen or sulphur, R₁₂ is linearor branched C₁₋₁₈ alkyl, hydroxy, linear or branched C₁₋₁₈ alkoxy,aralkyloxy or NR₁₃R₁₄, where R₁₃ and R₁₄, which may be the same ordifferent, are hydrogen, linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₄₋₆ cycloalkylalkyl, each of the latter three groups being optionallysubstituted by up to three fluorine atoms or hydroxy group when C_(≧2),C₃₋₆ alkenyl, aryl, aralkyl or an optionally substituted heterocyclicring or R₁₃ and R₁₄ may form together a C₃₋₆ alkyl ring which may beinterrupted by an oxygen or a NR₁ where R₁ has the same meaningdescribed above,

or R₆ is a CH₂WA group, where W is oxygen, sulphur or NR₁₄, and A ishydrogen, linear or branched alkyl or COR₁₄, where R₁₄ is defined aboveand is preferably methyl; or R₆ is a COCOR₁₂ group, where R₁₂ has thesame meaning described above, and is preferably C₁₋₁₈ alkoxy;

or R₆ is a NR₁₃R₁₄ group, where R₁₃ and R₁₄ have the same meaningdescribed above, or R₁₃ may be a (CH2)mCOR group where m and R have thesame meanings defined above;

or R₆ is a P(Z)R₁₂ group where Z and R₁₂ have the same meaning describedabove, and preferably Z=O and R12=C₁₋₁₈ alkoxy;

or R₆ is a S(O)_(i)R₁₂ group where i=1,2 and R₁₂ has the same meaningdescribed above. R₇ is hydrogen, C₁₋₁₈ alkyl, C₂₋₁₈ alkenyl, halogen,halogen-C₁₋₆ alkyl, (CH₂)_(m)COR where m and R have the same meaningsdefined above or is a group

 or a five- or six-membered heteroaromatic group, containing up to threeheteroatoms such as O, S and N, substituted with R₃ in which R₃ has thesame meaning described above,

R₈ is hydrogen, C₁₋₆ alkyl preferably methyl;

n is 0 or 1;

when n=0, then X and Y are independently oxygen, sulphur, CH or a R6- orR7-substituted carbon atom, and NR₉, where R₉ is hydrogen, linear orbranched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkylalkyl, each of thelatter three groups being optionally substituted by a hydroxy group whenC_(≧2), or may contain a NR₁₀R₁₁ group where R₁₀ and R₁₁ have the samemeaning described above, C₃₋₅ alkenyl, aryl, aralkyl or (CH₂)_(m)CORwherein m is 0 to 5 and R represents hydroxy, C₁₋₅ alkoxy, OC₃₋₆ alkenylor alkylaryl, NR₁₀R₁₁ where R₁₀ and R₁₁ may be the same or different,are each hydrogen, linear or branched C₁₋₆ alkyl, C₄₋₆ cycloalkylalkyl;and when n=1, then X and Y are both N, or N and CH.

When R₁ is aryl, it is preferably phenyl and when it is aralkyl, it ispreferably phenyl-C₁₋₆ alkyl.

Examples of R₁ are hydrogen, methyl, ethyl, propyl, i-propyl, allyl,benzyl, phenyl-ethyl, CH₂CH₂OH, CH₂COOH, CH₂COOEt, CH₂CONH₂, and COMe.

Examples of R₂ are hydrogen, hydroxy and methoxy.

Examples of R₃ are hydrogen, hydroxy, ethyl, bromine, hydroxy, methoxy,ethoxy, i-propoxy, COMe and OCH₂COOH.

Examples of R₄ and R₅ are hydrogen, hydroxy, acetyloxy, methoxy,O-phenyl, together as an oxy group or R₄ together with R₃ is amethylendioxy group.

Examples of R₆ are CONH₂, CONMe₂, CONEt₂, CON(i-Pr)₂, CON(i-Pr)CH₂Ph,CON(i-Pr)(CH₂)₂OH, CON(CH₂CF₃)(i-Pr), COOMe, COOEt, COO-n-Pr, COO-i-Pr,and COO-i-Bu, COOCH(i-Pr)₂, CSNEt₂, CSN(i-Pr)₂, COOH, COMe, CO-i-Pr,CO-i-Bu, CO-t-Bu, CO-3-pentyl, COPh,

and PO(OEt)₂.

Examples of R₇ are methyl, i-propyl, trifluoromethyl, CH₂COOH andCH₂COOEt.

An example of R₈ is hydrogen.

Examples of R₉ are hydrogen, methyl, CH₂COOH, CH₂COOEt, CH₂CONHCH₂Ph,CH₂CONHMe, CH₂CONMe₂.

Examples of X are NR₉, where R₉ are the same of the examples describedabove, and S.

Examples of Y are CR₇, where R₇ are the same of the examples describedabove.

A group of preferred compounds of formula (I) is that in which n=0, X isNH and Y is CH or a R₆- or R₇-substituted carbon atom, where R₆ is agroup —C(Z)—R₁₂ where R₁₂ is C₁₋₆ alkyl, C₁₋₄ alkoxy or NR₁₃R₁₄ whereR₁₃ and R₁₄ are as defined above and Z is oxygen; and R₇ is methyl orhalogen-C₁₋₂alkyl.

Particularly preferred compounds of formula (I) are those in which R₆ isCONEt₂, CON(i-Pr)₂ or COO-i-Bu, R₇ is methyl, and R₉ is hydrogen, methylor CH₂COOH.

The compounds of formula (I) or their salts or solvates are preferablyin pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, of apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excludingnormal pharmaceutical additives), preferably 75%, more preferably 90%and still more preferably 95% of the compound of formula (1) or its saltor solvate.

One preferred pharmaceutically acceptable form is the crystalline form,including such form in a pharmaceutical composition. In the case ofsalts and solvates the additional ionic and solvent moieties must alsobe non-toxic.

Examples of pharmaceutically acceptable salts of a compound of formula(I) include the acid addition salts with the conventional pharmaceuticalacids, for example, maleic, hydrochloric, hydrobromic, phosphoric,acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric,succinic, benzoic, ascorbic and methanesulphonic.

The compounds of formula (I) may exists in more than one stereoisomericform, and the invention extends to all such forms as well as to theirmixtures thereof, including racemates.

The invention also provides a process for the preparation of a compoundof formula (I), or a solvate or salt thereof, which comprises condensinga compound of formula (a), where K is H, Br, COR₇, ═CHOH or ═NOH, with acompound of formula (b), where Q is COR₇, CHClR₇, COR₇, SH or NH₂, and Jis ═NNHPh, ═O, ═H₂, or ═CHR, where R₇ and R₆ have the same meaningdescribed above.

and optionally thereafter converting the compound of formula (I) to asolvate or salt thereof.

Preferred reaction conditions when K=H, Q=COR₇ and J=═NNHPh are AcOH/Znin presence of AcONa at the temperature in a range of 60-100° C.;

Preferred reaction conditions when K=COR₇, Q=SH and J=═H₂ are i) dry HClin alcoholic media at RT, ii) strong base e.g. MeONa in MeOH.

Preferred reaction conditions when K=H, Q=CHClR, and J=═O are NaH inTHF.

The compounds of formula (I), or salts or solvates thereof, may beprepared by the methods illustrated in the following general reactionschemes, or by modification thereof, using readily available startingmaterials, reagents and conventional synthetic procedures. If aparticular enantiomer of a compound of the present invention is desired,it may be synthesised starting from the desired enantiomer of thestarting material and performing reactions not involving racemizationprocesses or it may be prepared by chiral synthesis, or by derivationwith a chiral auxiliary, where the resulting diastereomeric mixture isseparated and the auxiliary group cleaved to provide the pure desiredenantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxy, diastereomeric salts are formed with an appropriate opticallyactive acid or base, followed by resolution of diastereomeric salts byfractional crystallization and subsequent recovery of the pureenantiomers.

Compounds (I) in which n=0, X=NH and Y is a R₇-substituted carbon atom,may be obtained starting from ketones of formula (II) and hydrazones offormula (III) (Organic Reactions, 1959, 3-142), in the presence of Znand CH₃COONa in CH₃COOH as solvent (Khimiya Geterot. Soed., 1972, 342)as described in scheme 1:

Compounds (1) in which n=0, X=NH and Y is a R₆-substituted carbon atom,may be obtained by cyclization of halogeno ketones of formula (IV) (J.Org. Chem, 1964, 29, 3459), with ketones of formula (V) in the presenceof NH₄OH (Can. J. Chem., 1970, 48, 1689) as described in scheme 2:

Compounds (I) in which n=0, X=O and Y is a R₇-substituted carbon atom,may be obtained by cyclising ketones of formula (II) withα-halogenoketones (preferably α-chloroketones) of formula (VI), in thepresence of a base (J. Org. Chem., 1984, 49, 2317) as described inscheme 3:

Compounds (I) in which n=0, X=O and Y is a R₆-substituted carbon atom,may be obtained by cyclization of the bromoketones (IV) with ketones (V)in ethanol in the presence of a base (preferably EtONa) (J. Chem. Soc.Perkin I, 1972, 2372) as described in scheme 4:

Compounds (I) in which n=0, X=S and Y is a R₇-substituted carbon atom,may be prepared from β-diketones of general formula (VII) (synthesisedby Claisen reaction, starting from ketones (II) and esters of formulaR₇-COOEt; J. Am. Chem. Soc., 1945, 67, 1510; J. Med. Chem. 1982, 25,983) and mercapto derivatives of formula (VIII) in the presence of HCl(DE 1.088.507; C.A., 1962, 56, 456; Synthesis, 1992, 526) as describedin scheme 5:

Compounds (I) in which n=0, Y=S and X is a R₆-substituted carbon atom,may be obtained by reacting α-mercaptoketones (IX) (which may beprepared starting from the bromoketones (IV) and H₂S/KOH, J. Am. Chem.Soc., 1985, 107, 4175) with an alkyne derivative of formula (X), in asolvent such as DMSO, in the presence of a base such as t-BuOK (ChemBer., 1964, 97, 2109) as described in scheme 6:

Compounds (I) in which n=0, X and Y are both N, may be obtained fromhydroxyimino derivatives (XV) and R₆-R₇-substituted imidoyl chlorides offormula (XVI) in basic media, and subsequent treatment of theintermediates with H⁺ in refluxing toluene (J. Org. Chem., 1993. 58,7092) as described in the scheme 7:

Compounds (I) in which n=1, X=N and Y=CH may be obtained by reactingα-hydroxymethylenketones (XI) (which may be prepared from ketones (II)by condensation with HCOOEt in the presence of a base; Org. Synth.Coll., 1963, 4, 536) with enamines (XII) (J. Ind. Chem. Soc., 1935, 12,289) as described in scheme 8:

Compound (I) in which n=1, and X=Y=N may be obtained starting fromα-hydroxyiminoketones (XIII) (which may be prepared from ketones (II)and i-amylnitrite/t-BuOK as described in J. Med. Chem., 1991, 34, 1715)with ethanediamines (XIV) and subsequent aromatization of theintermediate in basic media (Chem. Ber., 1967, 100, 555) as described inscheme 9:

Compound of general formula (I′) in which n=0, X=NH and Y is a R₆- orR₇-substituted carbon atom may be converted using an alkylating agentR₉Br in the presence of NaH in DMF to obtain other compounds of generalformula (I) in which the pyrrole nitrogen is substituted with a R₉ groupas generally described in Scheme 10.

Compound of general formula (I′) in which R₄=OH and R₅=H may be preparedfrom known ketones of formula (II) according to the Schemes describedabove or, alternatively, from compounds of general formula (I) in whichR₄ and R₅ together form an oxy group (—O—), by reaction with Zn inboiling MeOH/HCl or boiling AcOH as described in the Scheme 11.

Compounds (I) in which n=0, X=S and Y=N, R6 is NR13R14 where R13 is(CH2)mCOR group where m=0 and R14 is hydrogen, may be obtained bycyclization of the bromoketones (IV) with thiourea in i-PrOH in thepresence of a base (preferably Na2CO3) (J. Chem. Soc., 1945, 455) andsubsequent acylation of the resulting amine with the appropriate acylchloride or with the corresponding carboxylic acid in presence of acoupling reagent such as DCC as described in Scheme 12:

Compounds of general formula (I) in which R₆ ia a group C(Z)R₁₂, inwhich Z is sulphur may be prepared from compounds in which Z is oxygenby reaction with thiation agents such as Lawesson reagent.

Compounds of general formula (I) in which R₆=CH₂WA may be prepared fromcompounds of general formula (I) by conventional chemical reactions wellknown in literature of groups R₆ such as esters amides, tioamides.

The compounds of formula (I) may be converted into theirpharmaceutically acceptable salts by reaction with the appropriateorganic or mineral acids.

Solvates of the compounds of formula (I) may be formed bycrystallization or recrystallization from the appropriate solvent. Forexample, hydrates may be formed by crystallization or recrystallizationfrom aqueous solutions, or solutions in organic solvents containingwater.

Also salts or solvates of the compounds of formula (I) which are notpharmaceutically acceptable may be useful as intermediates in theproduction of pharmaceutically acceptable salts or solvates. Accordinglysuch salts or solvates also form part of this invention.

In general compounds of formula (I) acting as selective delta receptorligands may be useful as analgesics, immunosuppressants to preventrejection in organ transplant and skin graft, anti-allergic andanti-inflammatory agents, brain cell protectant, for the treatment ofdrug and alcohol abuse, to decrease gastric secretion, for the treatmentof diarrhoea, cardiovascular and respiratory diseases, cough andrespiratory depression, mental illness, epileptic seizures and otherneurologic disorders (herein after referred to as ‘Conditions’). Inparticular, the activity of the compounds of formula (I) as deltaagonists in standard tests indicates that they are of potentialtherapeutic utility as analgesic agents for the amelioration orelimination of pain.

Accordingly the present invention also provides a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, for useas an active therapeutic substance.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for the treatment of the Conditions.

Such a medicament, and a composition of this invention, may be preparedby admixture of a compound of the invention with an appropriate carrier.It may contain a diluent, binder, filler, disintegrant, flavouringagent, colouring agent, lubricant or preservative in conventionalmanner.

These conventional excipients may be employed for example as in thepreparation of compositions of known agents for treating the Conditions.

Preferably, a pharmaceutical composition of the invention is in unitdosage form and in a form adapted for use in the medical or veterinarialfields. For example, such preparations may be in a pack form accompaniedby written or printed instructions for use as an agent in the treatmentof the Conditions.

The suitable dosage range for the compounds of the invention depends onthe compound to be employed and on the condition of the patient. It willalso depend, inter alia, upon the relation of potency to absorbabilityand the frequency and route of administration.

The compound or composition of the invention may be formulated foradministration by any route, and is preferably in unit dosage form or ina form that a human patient may administer to himself in a singledosage. Advantageously, the composition is suitable for oral, rectal,topical, parenteral, intravenous or intramuscular administration.Preparations may be designed to give slow release of the activeingredient.

Compositions may, for example, be in the form of tablets, capsules,sachets, vials, powders, granules, lozenges, reconstitutable powders, orliquid preparations, for example solutions or suspensions, orsuppositories.

The compositions, for example those suitable for oral administration,may contain conventional excipients such as binding agents, for examplesyrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone;fillers, for example lactose, sugar, maize-starch, calcium phosphate,sorbitol or glycine; tabletting lubricants, for example magnesiumstearate; disintegrants, for example starch, polyvinyl-pyrrolidone,sodium starch glycollate or microcrystalline cellulose; orpharmaceutically acceptable setting agents such as sodium laurylsulphate.

Solid compositions may be obtained by conventional methods of blending,filling, tabletting or the like. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fibers. When the composition is in theform of a tablet, powder, or lozenge, any carrier suitable forformulating solid pharmaceutical compositions may be used, examplesbeing magnesium stearate, starch, glucose, lactose, sucrose, rice flourand chalk. Tablets may be coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.The composition may also be in the form of an ingestible capsule, forexample of gelatin containing the compound, if desired with a carrier orother excipients.

Compositions for oral administration as liquids may be in the form of,for example, emulsions, syrups, or elixirs, or may be presented as a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Such liquid compositions may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcerlulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; aqueous or non-aqueousvehicles, which include edible oils, for example almond oil,fractionated coconut oil, oily esters, for example esters of glycerine,or propylene glycol, or ethyl alcohol, glycerine, water or normalsaline; preservatives, for example methyl or propyl p-hydroxybenzoate orsorbic acid; and if desired conventional flavouring or colouring agents.

The compounds of this invention may also be administered by a non-oralroute. In accordance with routine pharmaceutical procedure, thecompositions may be formulated, for example for rectal administration asa suppository. They may also be formulated for presentation in aninjectable form in an aqueous or non-aqueous solution, suspension oremulsion in a pharmaceutically acceptable liquid, e.g. sterilepyrogen-free water or a parenterally acceptable oil or a mixture ofliquids. The liquid may contain bacteriostatic agents, anti-oxidants orother preservatives, buffers or solutes to render the solution isotonicwith the blood, thickening agents, suspending agents or otherpharmaceutically acceptable additives. Such forms will be presented inunit dose form such as ampoules or disposable injection devices or inmulti-dose forms such as a bottle from which the appropriate dose may bewithdrawn or a solid form or concentrate which can be used to prepare aninjectable formulation.

The compounds of this invention may also be administered by inhalation,via the nasal or oral routes. Such administration can be carried outwith a spray formulation comprising a compound of the invention and asuitable carrier, optionally suspended in, for example, a hydrocarbonpropellant

Preferred spray formulations comprise micronised compound particles incombination with a surfactant, solvent or a dispersing agent to preventthe sedimentation of suspended particles. Preferably, the compoundparticle size is from about 2 to 10 microns.

A further mode of administration of the compounds of the inventioncomprises transdermal delivery utilising a skin-patch formulation. Apreferred formulation comprises a compound of the invention dispersed ina pressure sensitive adhesive which adheres to the skin, therebypermitting the compound to diffuse from the adhesive through the skinfor delivery to the patient. For a constant rate of percutaneousabsorption, pressure sensitive adhesives known in the art such asnatural rubber or silicone can be used.

As mentioned above, the effective dose of compound depends on theparticular compound employed, the condition of the patient and on thefrequency and route of administration. A unit dose will generallycontain from 20 to 1000 mg and preferably will contain from 30 to 500mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.The composition may be administered once or more times a day for example2, 3 or 4 times daily, and the total daily dose for a 70 kg adult willnormally be in the range 100 to 3000 mg. Alternatively the unit dosewill contain from 2 to 20 mg of active ingredient and be administered inmultiples, if desired, to give the preceding daily dose.

No unacceptable toxicological effects are expected with compounds of theinvention when administered in accordance with the invention.

The present invention also provides a method for the treatment and/orprophylaxis of the Conditions in mammals, particularly humans, whichcomprises administering to the mammal in need of such treatment and/orprophylaxis an effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof.

The activity of the compounds of the present invention as selectivedelta ligands is determined in radioligand binding assays as describedbelow.

Mouse brain membranes were prepared as described by Kosterlitz (Br. J.Pharmacol., 1981, 73, 939.). The binding of the preferential deltaligand [³H]-[D-Ala²,D-Leu⁵]-enkephalin (DADLE) was evaluated at itsK_(D) concentration (1.3 nM) in presence of 40 nM of the unlabelled muligand [D-Ala², MePhe⁴, Gly-ol⁵]-enkephalin (DAMGO). The binding of themu ligand [³H]-DAMGO (Eur. J. Pharmacol., 1989, 166, 213) and of thekappa ligand [³H]-U69593 (Excerpta Medica, 1990, 211) were carried outat 0.5 nM. The non-specific binding was determined in presence ofnaloxone (10 μM) for all tritiated ligands. Binding data were expressedas percentage of inhibition and fitted the following equation:f(x)=100·X/(IC₅₀+X) where X are cold drug concentration values. The IC₅₀obtained were used to calculate the inhibitory constants (K_(i))accordingly to the Cheng and Prusoff relation (Biochem. Pharmacol.,1973, 22, 3099).

The delta agonistlantagonist activity of the compounds of the presentinvention is determined in the cAMP bioassay in NG108-15 cell lines asdescribed below.

NG 108-15 cell were grown at 37° C. in humidified atmosphere of 5% CO₂and 95% air in DMEM (without sodium pyruvate using 4500 mg/l glucose)supplemented with 10% foetal calf serum containing 2 mM glutamine, 2%HAT×50 supplement, 50 μg streptomycin and 50 I.U. penicillin per mlconfluent cells were harvested with 1M EDTA in Ca/Mg-freephosphate-buffered saline with mechanical stiring. Medium was replacedevery 2 day. One day before the experiment the cells were dispensed in17 mm culture plate (about 10×10⁶ cells/plate). After 1 day, the growthmedium was removed and cells washed twice with a modified Krebs-Ringermedium buffered with hepes-NaOH 200 mM, pH 7.4, that contained (mmol/l):NaCl (125), KCl (5), KH₂PO₄ (0.4), MgSO₄ and CaCl₂ (1.2) NaHCO₃ (25),glucose (12). Incubation medium was also including 1 mM3-isobuthyl-1-methylxantine (IBMX). Experiments were performed at roomtemperature. After incubation for 10 minutes to allow IBMXincorporation, NG108-15 cells were exposed to 1 μM forskolin and thecompound to be tested, for 10 minutes. The reaction was terminated byadding cold 0.4N HClO₄. After 15 minutes, the cold surnatants werecarefully collected and neutralised using 1M KC₂O₃. After an overnightincubation at 4° C. the tubes were centrifuged at 9000 rpm for 5 minutesand a 100 μl aliquot tested for cAMP content by using the commerciallyavailable ¹²⁵I cAMP RIA kit (Amersham Inc.). The pellets from theoriginal plates were dissolved in NaOH 0.5N and the protein content wasdetermined with the method described by Bradfort (Anal. Biochem. 1976,72, 248). The data were normalised to protein content.

The most potent compounds described in the present invention showedaffinities for the delta receptor ranging from 0.5 to 200 nM with deltaselectivity ranging from 20 to 1500 times in respect to the other opioidreceptor types. These compounds displayed also potent delta agonist orantagonist properties in the cAMP inhibition bioassay. Selective deltaagonists (antagonised by the selective delta antagonist naltrindole)displayed IC₅₀s ranging from 1 to 500 nM. For example, the compound ofExample 10 shows a Ki delta=2.9 nM, Ki mu/Ki delta=840 and Ki kappa/Kidelta=600. The compound of Example 1 showed an agonist activity in theinhibition of forskolin-stimulated cAMP in NG108-15 cells (IC₅₀=15 nM)completely antagonised by the selective delta antagonist naltrindole(100 nM).

Mouse abdominal constriction (MAC) (Proc. Soc. Exp. Biol. Men, 1957, 95,729), mouse tail-flick (MTF) (J. Pharm. Exp. Ther., 1941, 72, 74) andmouse tail-flick warm water (MTF-WW) (Life Sci., 1986, 32, 1795) wereadopted to evaluate the antinociceptive efficacy of the compounds of thepresent invention.

The following preparations 1 to 7 illustrate the synthetic procedure toobtain new ketones of general formula (II) that, as such, form a part ofthe present invention. In particular4,5-epoxy-17-methyl-3-vinylmorphinan-6-one,4,5-epoxy-3-(1-ethoxyvinyl)-17-methylmorphinan-6-one,4,5-epoxy-3-ethyl-17-methylmorphinan-6-one,3-bromo-4,5-epoxy-14-hydroxy-17-methylmorphinan-6-one and3-bromo-4,5-epoxy-17-methylmorphinan-6-one are novel compounds and areutilised as starting materials to prepare the compounds of Examples 28,30, 33, 35, 41, 52, 61 and 64. Other ketones used as starting materialsare known in the literature. Preparation 8 illustrates the preparationof a new phosphonohydrazone of general formula (III) that was used asstarting material to prepare the compound of Example 89. Example 1illustrates the preparation of compounds of general formula (I) of thepresent invention starting from the corresponding ketones of generalformula (II) and the corresponding known hydrazones of general formula(III). Examples 2, 49 and 52 illustrate the preparation of compounds ofgeneral formula (I) which are in turn prepared by chemicaltransformation of the corresponding compounds of formula (I). Example105 describes the preparation of compounds of general formula (I) inwhich n=0, X=S and Y is a substituted carbon atom. The Examplesdescribed herein are prepared according to the same procedures asdescribed for Examples 1, 2, 49, 52 and 105.

The compounds of the Examples 1 to 105 are summarised in the ChemicalTable.

General procedure for the preparation of compounds of general formula(II) in which R₃=CH═CH₂ and C(OEt)═CH₂.

Preparation 1

4,5-Epoxy-17-methyl-3-trifluoromethanesulfonyloxymorphinan-6-one

5.5 g (19.3 mmol) of 4,5-epoxy-3-hydroxy17-methylmorphinan-6-one weredissolved in 20 ml of pyridine under a nitrogen atmosphere. The solutionwas cooled to 0° C. and 3.56 ml (21.2 mmol) of trifluoromethanesulfonicanhydride were added dropwise. The solution was stirred for 5 min at 0°C. and then allowed to warm to room temperature overnight. The reactionmixture was poured onto water and the aqueous phase was extracted withAcOEt. The organic phase was dried over NA₂SO₄ and the solvent removedin vacuo. The crude reaction mixture was purified by flashchromatography, eluting with a mixture CH₂Cl₂/MeOH/conc. NH₄OH 90:7:0.7respectively, yielding 6.26 g of the title product.

N.M.R. 300 MHz (CDCl₃): δ7.0 (d, 1H), 6.7 (d, 1H), 4.7 (s, 1H), 3.2 (m,1H), 3.1 (d, 1H), 2.7-2.3 (m, 8H), 2.1 (m, 2H), 1.9-1.7 (m, 2H), 1.3-1.1(m, 1H).

MS (TSP) m/z=417.2 (M⁺)

Preparation 2

4,5-Epoxy-17-methyl-3-vinylmorphinan-6-one

2 g (4.8 mmol) of4,5-epoxy-17-methyl-3-trifluoromethanesulfonyloxymorphinan-6-one weredissolved, under a nitrogen atmosphere, in 25 ml of dimethylformamide,then 1.46 ml (5 mmol) of vinyltributyltin, 1.6 g (38.4 mmol) of LiCl,0.337 g (0.48 mmol) of bis(triphenylphosphine)palladium(II) chloride and0.5 g (1.9 mmol) of triphenylphosphine were added. The reaction mixturewas heated to 100° C. for 3 h, then it was poured onto water and theaqueous phase was extracted with AcOEt. The organic phase was dried overNa₂SO₄ and the solvent was removed in vacuo. The crude reaction mixturewas purified by flash chromatography, eluting with a mixtureCH₂Cl₂/MeOH/conc. NH₄OH 90:7:0.7 respectively, yielding 1.1 g of thetitle product.

N.M.R. 300 MHz (CDCl₃): δ7.1 (d, 1H), 6.8-6.6 (m, 2H), 6.0 (d, 1H), 5.4(d, 1H), 4.6 (s, 1H), 3.2-1.7 (m, 13H), 1.2 (m, 2H).

MS (TSP) m/z=295.1 (M⁺)

Preparation 3

4,5-Epoxy-3-(1-ethoxyvinyl)-17-methylmorphinan-6-one

2.5 g (6.0 mmol) of4,5-epoxy-17-methyl-3-trifluoromethanesulfonyloxymorphinan-6-one, 2.1 ml(6.2 mmol) of (1-ethoxyvinyl)tributyltin, 2 g (48 mmol) of LiCl, 0.42 g(0.6 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.63 g(2.4 mmol) of triphenylphosphine in 25 ml of dimethylformamide weretreated as described in Preparation 2. The crude reaction mixture waspurified by flash chromatography, eluting with a mixtureCH₂Cl₂/MeOH/conc. NH₄OH 90:7:0.7 respectively, yielding 1.95 g of thetitle product.

I.R. (KBr): 2932, 1728, 1674 cm⁻¹.

N.M.R. 300 MHz (CDCl₃): δ7.4 (d, 1H), 6.6 (d, 1H), 5.2 (s, 1H), 4.65 (s,1H), 4.45 (s, 1H), 3.9 (q, 2H), 3.2-1.4 (m, 18H).

MS (TSP) m/z=339.1 (M⁺).

Preparation 4

4,5-Epoxy-3-ethyl-17-methylmorphinan-6-one

1.2 g (4.06 mmol) of 4,5-epoxy-17-methyl-3-vinylmorphinan-6-one weredissolved in 150 ml of absolute EtOH. 1 g of 10% Pd on charcoal wasadded and the reaction mixture was hydrogenated in a Parr apparatus at35 psi and at room temperature for 8 h. The catalyst was filtered offand the solvent was removed in vacuo, yielding 0.77 g of the titleproduct.

N.M.R. 300 MHz (CDCl₃): δ6.9 (d, 1H), 6.6 (d, 1H), 4.6 (s, 1H), 3.2-1.7(m, 18H), 0.9 (m, 2H).

MS (TSP) m/z=297.1 (M⁺)

General procedure for the preparation of compounds of general formula(II) in which R₃=Br

Preparation 5

3-Bromo4,5-epoxy-17-methylmorphinan-6-ol

3.1 g (11.4 mmol) of 4,5-epoxy-17-methylmorphinan-6-ol were dissolved in150 ml of glacial acetic acid and 11.4 ml of a 1M solution of Br₂ inAcOH were added dropwise. After 1 h, AcOH was removed in vacuo, theresidue was taken up with water, the aqueous solution was brought to pH7 with a saturated NAHCO₃ solution and extracted with AcOEt. The organicphase was dried over NA₂SO₄, the solvent was removed in vacuo, yielding3.6 g of the title product.

I.R. (KBr): 3580, 2930, 1452 cm⁻¹.

N.M.R. 300 MHz (CDCl₃): δ7.2 (d, 1H), 6.6 (d, 1H), 4.6 (d, 1H), 4.0 (m,1H), 3.1 (m, 1H), 2.9 (d, 1H), 2.5-1.5 (m, 12H), 1.1 (m, 1H).

MS (TSP) m/z=349.0 (M−1)

Preparation 6

3-Bromo-4,5-epoxy-14-hydroxy-17-methylmorphinan-6-one

1.1 g (3.8 mmol) of 4,5-epoxy-14-hydroxy-17-methylmorphinan-6-one in 50ml of glacial AcOH were treated with 3.8 ml of a 1M solution of Br₂ inAcOH as described in Preparation 5, yielding 1.1 g of the title product.

I.R. (KBr): 3348, 2910, 1738 cm⁻¹.

Preparation 7

3-Bromo-4,5-epoxy-17-methylmorphinan-6-one

A solution of 1.6 ml of DMSO in 4.8 ml of CH₂Cl₂ was added slowly, undera nitrogen atmosphere and at −55° C., to a solution of 0.9 ml of oxalylchloride in 21 ml of CH₂Cl₂. After 2 min. 3.6 g (10.3 mmol) of3-bromo-4,5-epoxy-17-methylmorphinan-6-ol in 20 ml of CH₂Cl₂ were added,followed, after 15 min. by 6.6 ml of Et₃N. The reaction mixture wasallowed to warm up to room temperature in 2 h, then it was quenched with50 ml of H₂O. The phases were separated, the organic phase was driedover NA₂SO₄ and the solvent was removed in vacuo. The crude reactionmixture was purified by flash chromatography, eluting with a mixtureCH₂Cl₂/MeOH/conc. NH₄OH 90:7:0.7 respectively, yielding 2.87 g of thetitle product.

I.R. (KBr): 2940, 1716, 1446 cm⁻¹.

N.M.R. 300 MHz (CDCl₃): δ7.2 (d, 1H), 6.6 (d, 1H), 5.4 (s, 1H), 3.3 (m,1H), 2.95 (d, 1H), 2.6-1.7 (m, 12H), 1.2 (m, 1H).

MS (TSP) m/z=347.0 (M−1)

Preparation 8

Diethyl-1-phenylhydrazono-2-oxopropylphosphonate

To a solution of 5.0 g (0.0257 mol) of diethyl(2-oxopropyl)phosphonatein 25 ml of ethanol/water 4:1, were added 7.1 g (0.0517 mol) of K₂CO₃and 0.0257 mol of phenyldiazonium chloride at 10° C. The resultingsuspension was stirred until the temperature reached the roomtemperature. Then 30 ml of water and ml 100 of CH₂Cl₂ were added. Theorganic layer was dried on Na₂SO₄ and evaporated in vacuo yielding 7 gof the title compound as red oil which was used as such in thesubsequent step. C₁₃H₁₉N₂O₄P

IR (neat): 3498, 1716, 1666, 1268, 1026 cm⁻¹.

N.M.R. 300 MHz (CDCl₃): δ12.9 (bs, 1H); 7.5-7.0 (m, SH), 4.2 (m, 4H);2.3 (s, 3H); 1.5 (m, 6H).

EXAMPLE 1[R-(4bS*,8α,s8aβp,12βp)]11(N-N-benzylN-isopropylaminocarbonyl)-7,10dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H){4,8methanobenzofuro[3,2]pyrrolo[2,3-g]soquinolinehydrochloride

0.65 g (2.17 mmoles) of 7,8-dihydrocodeinone hydrochloride, 2.2 g (6.51mmoles) di N-benzyl-N-isopropyl-2-phenylhydrazone-3-oxobutkamide, weredissolved in a mixture of 10 ml di glacial acetic acid and 0.54 g (6.51mmoles) of CH₃COONa The resulting reaction mixture was warmed to 60° C.,then 0.57 g (8.6 mmoles) of Zn dust were added portionwise and undernitrogen atmosphere. The mixture was refluxed for 2 h, and then cooledto room temperature. The resulting salts were eliminated by decantationand washed with acetic acid. The acidic solutions were collected andthen brought to pH 8 and extracted several times with AcOEt. The organicphase was dried and evaporated to dryness in vacuo. The resultingresidue was purified by medium pressure chromatography using silica gel(15-25 ) and a mixture of AcOEt/MeOH/NH4OH conc. 90:10:0.5 as eluenL Theproduct was taken up in a mixture of acetone tMeOH 1:1 and the solutionwas brought to acidic pH with HCl/Et₂O. The resulting precipitate wasfiltered, washed and dried yielding 0.5 g of the title compound.M.P.=304° C. dec.

EXAMPLE 2[8R-(4bS*,8α,8aβ,12bβ)]-11-Diethylaminothiocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinolinehydrochloride

1 g (2.3 mmoles) of[8R-(4bS*,8α,8aβ,12bβ)]-11-diethylaminocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline,0.950 g (2.3 mmoles) of the Lawesson reagent, were dissolved in 40 ml oftoulene and the mixture refluxed for 4 h. The solvent was removed invacuo, then the residue was taken up in CH₂Cl₂ and washed with s.s.NaHCO₃. The organic layer was dried on Na₂SO₄. After evaporation of thesolvent, the residue was purified with flash chromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH conc. 86:10:0.6) then the product was dissolvedin acetone. The resulting solution was brought to acidic pH withHCl/Et₂O. The precipitate was filtered, dissolved in boiling MeOH inpresence of charcoal for 30′. The charcoal was filtered off, and thesolution was evaporated to dryness. The residue was triturated. withboiling Et₂O yielding 0.41 g of the title compound. M.P.>250° C.

The compound of Example 73 was prepared according to the same proceduredescribed above.

EXAMPLE 49[8R-(4bS*,8α,8aβ,12b,β)]-11-Isopropylcarbonyl-7,10,12-trimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2e]pyrrolo[2,3-g]isoquinolinehydrochloride

0.52 g (1.2 mmoles) of[8R-(4bS*,8α,8aβ,12bβ)]-11-isopropylcarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline(Example 34) were dissolved in 5 ml of DMF under nitrogen atmosphere.0.051 g of 60% NaH was added portionwise maintaining the temperature of0° C. After 30′ a solution of 0.2 g of MeI dissolved in 1 ml of DMF wasadded dropwise. The reaction was quenched after 1 h with using crushedice. The resulting solution was exhaustively with Et₂O. The organiclayers were dried over Na₂SO₄ and then the solvent in vacuo. Theresulting residue was dissolved in acetone and the solution brought toacidic pH with Et₂O/HCl. The solvent was in turn evaporated and theresulting residue was triturated with boiling Et₂O. The solid wasfiltered, washed and dried to yield 0.25 g of the title compound. M.P.240-243° C.

The compounds of Examples 62 and 82 were prepared according to theprocedure described above.

The compounds of Examples 74, 79 and 80 were prepared following the sameprocedure using as alkylating agent ethylbromoacetate. The resultingethylesters were in turn hydrolysed in acidic conditions to thecorresponding acid derivatives of the above Examples.

EXAMPLE 52 [10R, 4bS-(4bb,9ab)]-3-Bromo-7-diisopropylaminocarbonyl-8,14-dimethyl-4b,5,9,9a,10,11-hexahydro-4-hydroxy-(6H)-10,4b-(iminoethano)phenanthro[3,2-b]pyrrole

0.3 g (0.58 mmol) of [8R-(4bS*,8a,8ab,12bb)]-1-bromo-11-diisopropylaminocarbonyl-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline(Example 30) were dissolved, under a nitrogen atmosphere, in 10 ml ofglacial AcOH and 0.15 g (1.8 mmol) of AcONa were added. The reactionmixture was heated to 80° C. and 0.23 g (3.5 mmol) of Zn dust were addedportionwise. The reaction mixture was heated to reflux for 4 h, then itwas poured onto ice, the pH was adjusted to 9 with conc. NH4OH and itwas extracted with CH2Cl2. The organic phase was dried over Na2SO4 andthe solvent was removed in vacuo. The crude reaction mixture waspurified by flash chromatography, eluting with a mixtureCH2Cl2/MeOH/conc. NH4OH 90:7:0.7 respectively. The resulting solid wastriturated in Et2O, yielding 0.15 g of the title product.

EXAMPLE 105[8R-(4bS*,8α,8aβ,12bβ)]-11-Methoxycarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,9,12b-hexahydro-4,8-methanobenzofuro[3,2-e]thieno[2,3-g]isoquinoline hydrochloride

A solution of 7-acetyl-4,5-epoxy-1-methoxy-17-methylmorphinan-6-one (1g, 2.9 mmol.) (J. Med. Chem. 1982, 25, 983) in MeOH (40 mL) was cooledat −10° C. and a stream of dry HCl was bubbled into the system untilsaturation (˜1 h.). Then, thioglycolic acid (0.4 mL, 5.8 mmol) wasadded, and the bubbling of HCl was continued at −10° C. for 4 h. Themixture was left at RT for 6 days. The solvent was evaporated in vacuo,the residue treated with conc. NH₄OH and extracted with AcOEt. Theorganic layer was separated, washed with water, dried (Na₂SO₄) andevaporated in vacuo. The crude product was directly used in the nextstep.

A 2N solution of MeONa (10 ml) was added to a solution of the aboveproduct in 12 ml MeOH was added and kept under nitrogen for 24 h. Thesolvent was evaporated and the residue treated with ice-cold water. Themixture was acidified with 6N HCl to pH=1. After washing with AcOEt theaqueous layer was treated with NaOH to pH=9 and extracted with AcOEt.The solvent was dried, evaporated and the crude product was purified bysilica gel chromatography (CH₂Cl₂/MeOH/conc. NH₄OH; 95:5:0.5). Theresulting product was treated with HCl/Et₂O yielding 55 mg of the titlecompound.

CHEMICAL TABLE

            Ex.             name             R₁             R₂            R₃             R₄             R₅

 1 [8R-(4bS*,8α,8aβ,12bβ)]-11-(N-Benzyl- N-isopropylaminocarbonyl)-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b- hexahyrdo-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3- g]isoquinoline hydrochloride Me HOMe —O—

 2 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diethylamminothiocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b- hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride Me HOMe —O—

 3 [10R,4bS-(4bβ,9aβ)]-7- Diethylaminocarbonyl-8,14-dimethyl-4-hydroxy-4b,5,9,9a,10,11-hexahydro- (6H)-[2,3-h]pyrrolo[10,4-b]iminophenantrene Me H H OH H

 4 [10R-4bS-(4bβ,9aβ)]-7- Diethylaminocarbonyl-3,4-dimethoxy-8,14-dimethyl-4b,5,9,9a,10,11- hexahydro-(6H)-[2,3-h]pyrrolo[10,4-b]iminophenantrene hydrochloride Me H OMe OMe H

 5 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diethylaminocarbonyl-1,8a-dimethoxy-7,10-dimethyl-5,6,7,8,12,12b- hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline Me OMe OMe —O—

 6 [8R-(4bS*,8α,8aβ,12bβ]-7,10-dimethyl-11-etoxycarbonyl-5,6,7,8,12,12b- hexahydro-4,8-methanobenzofuro[3,2-3]pyrrolo[2,3-g]isoquinoline hydrochloride Me OH OMe —O—

 7 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diethylaminocarbonyl-8a-hydroxy-1-methoxy-10-methyl-7-(2-propenyl)- 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride AllylOH OMe —O—

 8 [10R-4bS-(4bβ,9aβ)]-7- Diethylaminocarbonyl-8,14-dimethyl-3-methoxy-4-oxyphenyl-4b,5,9,9,a,10,11-hexahydro-(6H)-[2,3-h]pyrrolo[10,4- b]iminophenantrene Me H OH OPh H

 9 [10R-4bS-(4bβ,9aβ)]-7- Diethylaminocarbonyl-8,14-dimethyl-3-methoxy-4b,5,9,9,a,10,11-hexahydro- (6H)-[2,3-h]pyrrolo[10,4b]iminophenantrene Me H OMe H H

10 [8R-(4bS*,8α,8aβ,12bβ)]-11- Etoxycarbonyl-7-methyl-1-methoxy-10-trifluoromethyl-5,6,7,8,12,12b- hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline Me H OMe —O—

11 [8R-(4bS*,8α,8aβ,12bβ)]-11- Etoxycarbonyl-7-methyl-10-(1-methylethyl)-1-methoxy-5,6,7,8,12,12b- hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride Me HOMe —O—

12 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diethylcarbonyl-10-methyl-1-methoxy-5,6,7,8,12,12b-hexahydro-(9H)-4,8- methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride H H OMe —O—

13 [8R-(4bS*,8α,8aβ,12bβ)]-11-Benzoyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b- hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline Me H OMe —O—

14 [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3- g]isoquinoline-11-carboxy acidMe H OMe —O—

15 [8R-(4bS*,8α,8aβ,12bβ)-11- diethylaminocarbonyl-1-methoxy-10-methyl-7-(2-phenylethyl)-5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g]isoquinolinePhene thyl H OMe —O—

16 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diethylaminocarbonyl-7-ethyl-10-methyl-5,6,7,8,12,12b-hexahydro-(9H)- 4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline Et H OMe —O—

17 [8R-(4bS*,8α,8aβ,12bβ)]-11-Acetyl- 7,10-dimethyl-1-methoxy-11-(2-methylpropyl)ossicarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline Me H OMe —O—

18 [8R-(4bS*,8α,8aβ,12bβ)]-11- Isobutilcarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro- [9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Me H OMe —O—

19 [8R-(4bS*,8α,8aβ,12bβ)]-7-Benzil-11-diethylaminocarbonyl-10-methyl-1- methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3- g]isoquinoline benzil H OMe —O—

20 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diethylaminocarbonyl-7-isopropyl-10-methyl-1-methoxy-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline i-Pr H OMe —O—

21 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diethylaminocarbonyl-10-methyl-1-methoxy-7-isopropyl-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Pr H OMe —O—

22 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diisopropylaminocarbonyl-7,10-dimethyl-1-ethoxy-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Me H OEt —O—

23 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diisopropylaminocarbonyl-7,10-dimethyl-1-isopropyloxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g]isoquinolinehydrochloride Me H O-i-Pr —O—

24 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diisopropylaminocarbonyl-7-methyl-1-methoxy-10-trifluoromethyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline Me H OMe —O—

25 [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-isobuthylcarbonyl-10-methyl-1-methoxy- 5,6,7,8,12,12b-hexahydro-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline-(9H)-8a-olhydrochloride Allyl OH OMe —O—

26 [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11- isobuthylcarbonyl-10-methyl-5,6,7,8,12,12b-hexahydro-4,8- methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline-1,8a(9H)-diol hydrochloride Allyl OH OH —O—

27 [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-isobuthylcarbonyl-1-ethoxy-10-methyl- 5,6,7,8,12,12b-hexahydro-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline-(9H)-8a-olhydrochloride Allyl OH OEt —O—

28 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diisopropylaminocarbonyl-7,10-dimethyl-1-ethyl-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Me H Et —O—

29 [8R-(4bS*,8α,8aβ,12bβ)]-7,10-dimethyl-1-methoxy-11(3-methyl-1,2,4-oxadiazole-5-yl)-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline Me H OMe —O—

30 [8R-(4bS*,8α,8aβ,12bβ)]-1-Bromo-11-diisopropylaminocarbonyl-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8- methanobenzofuro[3,2-e]pyrolo[2,3-g]isoquinolin-8a-(9H)-ol hydrochloride Me OH Br —O—

31 [8R-(4bS*,8α,8aβ,12bβ)]-11- Ethoxycarbonyl-10-ethoxycarbonylmethylen-1-methoxy-7-methyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3- g]isoquinolin-8a-(9H)-olhydrochloride Me H OMe —O—

32 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- Dimethyl-1-methoxy-11-tertbuthylcarbonyl-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Me H OMe —O—

33 [8R-(4bS*,8α,8aβ,12bβ)]-1-Bromo-11- diisopropylaminocarbonyl-7,10-dimethyl-5,6,7,8,12,12b-hexahydro- [9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Me H Br —O—

34 [8R-(4bS*,8α,8aβ,12bβ)]-11- isopropylcarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo [2,3-g]isoquinoline hydrochloride MeH OMe —O—

35 [8R-(4bS*,8α,8aβ,12bβ)]-1-Bromo-7,10- dimethyl-11-isobuthylcarbonyl-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g]isoquinolinehydrochloride Me H Br —O—

36 [10R,4bS-(4bβ,9aα)]- 7diisopropylaminocarbonyl-8,14-dimethyl-4b,5,9,9a,10,11-hexahydro- [6H]-10,4b-(iminoethano)phenantro[3,2-b]pyrrole Me H H H H

37 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- Dimethyl-1-methoxy-11-(2-propyl)oxycarbonyl-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanolbenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Me H OMe —O—

38 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- Dimethyl-11-(1,1-dimethylethyl)oxycarbonyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g]isoquinolinehydrochloride Me H OMe —O—

39 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- Dimethyl-11-methoxycarbonyl-1-methoxy-11-5,6,7,8,12,12b-hexahydro- [9H]-4,8-methanobenzofuro[3,2-e]pyrrol[2,3-g]isoquinoline hydrochloride Me H OMe —O—

40 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- Dimethyl-1-methoxy-11-(1-propyl)oxycarbonyl-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Me H OMe —O—

41 [8R-(4bS*,8α,8aβ,12bβ)]-1-Acetyl-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-[9H]- 11-isobuthylcarbonyl-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3- g]isoquinoline hydrochloride Me HCOMe —O—

42 [8R-(4bS*,8α,8aβ,12bβ)]-11-Ethyloxayl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g]isoquinolinehydrochloride Me H OMe —O—

43 [10R,4bS-(4bβ,9aα)]-7- Isobuthylcarbonyl-8,14-dimethyl-4-hydroxy-3-methoxy-4b,5,9,9a,10,11- hexahydro-[6H]-10,4b-(iminoethano)phenantro[3,2-b]pyrrole hydrochloride Me H OMe OH H

44 [10R,4bS-(4bβ,9aα)]-14-Allyl-7-isobuthylcarbonyl-4-hydroxy-8-methyl-3-methoxy-4b,5,8,8a,10,11-hexahydro- [6H]-10,4b-(iminoethano)penantro[3,2-b]pyrrole-9a-ol hydrochloride Allyl OH OMe OH H

45 [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl-11-isobuthylcarbonyl-1-methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8- methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Allyl H OMe —O—

46 [10R,4bS-(4bβ,9aα)]-4-Acetoxy-7- diisopropylaminocarbonyl-8,14,dimethyl- 3-methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-10,4b-(iminoethano)phenantro[3,2- b]pyrrole Me H OMe OAc H

47 [10R,4bS-(4bβ,9aα)]-14-Allyl-7- isobuthylcarbonyl-8-methyl-3-methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-10,4b-(iminoethano)phenantro[3,2-b]pyrrole- 9a-ol hydrochloride Allyl OH—OCH₂O— H

48 [8R-(4bS*,8α,8aβ,12bβ)]-7,10-Dimethyl-1-methoxy-11-(penthyl-3-carbonyl)- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride Me HOMe —O—

49 [8R-(4bS*,8α,8aβ,12bβ)]-11- Isopropylcarbonyl-7,10,12-trimethyl-1-methoxy-5,6,7,7,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride Me H OMe —O—

50 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diisopropylaminocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro- [9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline-8a-(9H)-ol hydrochloride Me OH OMe —O—

51 [8R-(4bS*,8α,8aβ,12bβ)]-7,10,11- trimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro [3,2-e]pyrrolo[2,3-g]isoquinolinehydrochloride Me H OMe —O—

52 [8R-(4bS*,8α,8aβ,12bβ)]-3-Bromo-7-diisopropylaminocarbonyl-8,14-dimethyl-1-methoxy-4b,5,9,9a,10,11-hexahydro-4- hydroxy-[6H]-10,4b-(iminoethano)phenantro[3,2-b]pyrrole Me H Br OH H

53 [8R-(4bS*,8α,8aβ,12bβ)]-11- isopropylethanolaminocarbonyl-7,10-dimethyl-1-methoxy- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2- e]pyrrolo[2,3-g]isoquinoline Me H OMe —O—

54 [8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl- 11-disopropylaminocarbonyl-10-methyl-1-methoxy-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline Allyl H OMe —O—

55 [8R-(4bS*,8α,8aβ,12bβ)]-7- isobuthylcarbonyl-3-methoxy-8,14-dimethyl-4b,5,9,9a,10,11- hexahydro-4-hydroxy[6H]-10,4b-(iminoethano)phenantro[3,2- b]pyrrole Me H OMe OH H

56 [8R-(4bS*,8α,8aβ,12bβ)]-11- Disopropylaminocarbonyl-7-hydroxyethyl-1-methoxy-10- methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2- e]pyrrolo[2,3-g]isoquinoline (CH₃)₃OH HOMe —O—

57 [8R-(4bS*,8α,8aβ,12bβ)]-11- carboxamido-7,10-dimethyl-1-methoxy-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline Me H OMe —O—

58 [8R-(4bS*,8α,8aβ,12bβ)]-11-(N- Benzyl-N-isopropyl)aminocarbonyl-7,10-dimethyl-1- methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline-8a-(9H)-ol hydrochloride Me OH OMe —O—

59 [8R-(4bS*,8α,8aβ,12bβ)]-11- Isopropylethanoaminocarbonyl-8,14-dimethyl-4-hydroxy-3- methoxy-4b,5,9,9a,10,11-hexahydro-[6H]-[2,3-h]pyrrolo- [10,4b]-iminoethanophenantrene Me H OMeOH H

60 [8R-(4bS*,8α,8aβ,12bβ)]-11- Benzoyloxycarbonyl-7,10-dimethyl-1-methoxy- 5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride Me H OMe —O—

61 [8R-(4bS*,8α,8aβ,12bβ)]-1- Acetyl-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-[9H]- 11-(2-methylpropyl)oxycarbonyl-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride MeH COMe —O—

62 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diisopropylaminocarbonyl-7,10,12-trimethyl-1-methoxy- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride MeH OMe —O—

63 [8R-(4bS*,8α,8aβ,12bβ)]-11-(2,4- dimethyl-3-pentyloxy)carbonyl-7,10-dimethyl-1-methoxy- 5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline Me H OMe —O—

64 [8R-(4bS*,8α,8aβ,12bβ)]-1- Bromo-7,10-dimethyl-5,6,7,8,12,12b-hexahydro-[9H]- 11-(2-methylpropyl)oxycarbonyl4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline Me H Br —O—

65 [10R-4bS-(4bβ,9aβ)]-8,10- Dimethyl-4b,5,9,9a,10,11-hexahydro-[9H]-7-(2- methylpropyl)oxycarbonyl-10,4b-(iminoethano)phenantro[3,2-b] pyrrole hydrochloride Me H H H H

66 [8R-(4bS*,8α,8aβ,12bβ)]-7- Ethoxycarbonylmethylen-11-diisopropylaminocarbonyl-1- methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride CH₃COOEt H OMe —O—

67 [8R-(4bS*,8α,8aβ,12bβ)]-7- Oxycarbonylmethylen-11-diisopropylaminocarbonyl-1- methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline CH₃COOH H OMe —O—

68 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- Dimethyl-11-dimethylaminocarbonyl-1-methoxy-10-methyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride MeH OMe —O—

69 [10R-4bS-(4bβ,9aβ)]-8,14- Dimethyl-7-isobutyloxycarbonyl-3-methoxy-4b,5,9,9a,10,11- hexahydro-[6H]-[2,3-h]pyrrolo[10,4b]-iminoethanophenantrene hydrochloride Me H OMe H H

70 [8R-(4bS*,8α,8aβ,12bβ)]-11- Diisopropylaminocarbonyl-1-methoxy-10-methyl- 5,6,7,8,12,12b-hexahydro-[9H]-11-(2-methylpropyl)oxycarbonyl-4,8- methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline H H OMe —O—

71 [8R-(4bS*,8α,8aβ,12bβ)]-1- methoxy-7-methyl-10-oxycarbonyl-11-oxycarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline Me H OMe —O—

72 [8R-(4bS*,8α,8aβ,12bβ)]-7- Aminocarbonylmethyl-11-diisopropylaminocarbonyl-1- methoxy-10-methyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8- methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline CH₂CONH₂ H OMe —O—

73 [8R-(4bS*,8α,8aβ,12b-11- diisopropylaminotiocarbonyl-1-methoxy-7,10-dimethyl-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline Me H OMe —O—

74 [[8R-(4bS*,8α,8aβ,12b-7,10- dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinolin-12-yl] acetic acidhydrochloride Me H OMe —O—

75 [10R,4bS-(4bβ,9aβ)]-7- Diisopropylaminocarbonyl-8,14-dimethyl-4b,59,9a,10,11- hexahydro-9a-hydroxy-[6H]-10,4b-(iminoethano)phenantro [3,2-b]pyrrole Me OH H H H

76 [10R,4bS-(4bβ,9aβ)]-8,14- dimethyl-4b,59,9a,10,11-hexahydro-9a-hydroxy-7-(2- methylpropyl)oxycarbonyl-10,4b-(iminoethano)phenantro[3,2-b] pyrrole hydrochloride Me OH H H H

77 [10R,4bS-(4bβ,9aβ)]-14-Allyl-7- diisopropylcarbonyl-4b,59,9a,10,11-hexahydro-9a-hydroxy- 10,4b-(iminoethano)phenantro[3,2-b]pyrrole hydrochloride Allyl OH H H H

78 [8R-(4bS*,8α,8aβ,12bβ)-7-Allyl- 11-diisopropylaminotiocarbonyl-1-ethoxy-10-methyl-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinolin-8a-ol hydrochlorideAllyl OH OEt —O—

79 [[8R-(4bS*,8α,8aβ,12bβ)-11- diisopropylaminocarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinolin-12-yl] acetic acidhydrochloride Me H OMe —O—

80 [[8R-(4bS*,8α,8aβ,12bβ)-11-(N- Benzyl-N-isopropyl)aminocarbonyl-7,10-dimethyl-1- methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro[3,2-e]pyrrolo[2,3-g]isoquinolin-12-yl]acetic acid hydrochloride Me H OMe —O—

81 [[8R-(4bS*,8α,8aβ,12bβ)-7-Allyl- 11-(2-methylpropyl)oxy carbonyl-1-ethoxy-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinolin-8a-ol hydrochloride Allyl OHOEt —O—

82 [[8R-(4bS*,8α,8aβ,12bβ)-7,10,12- trimethyl-1-mthoxy-11-methyloxycarbonyl-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline Me H OMe —O—

83 [[8R-(4bS*,8α,8aβ,12bβ)-11- Diisopropylaminocarbonyl-7-acetoxy-10-methyl-1-methoxy- 5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline COMe H OMe —O—

84 [[8R-(4bS*,8α,8aβ,12bβ)-11- Diisopropylaminocarbonyl-4,8-diacetoxy-14-methyl-3-methoxy- 4b,5,9,9a,10,11-hexahydro-[6H]-[2,3-h]pyrrolo[10,11-b] iminoethanophenantrene COMe H OMe OH H—

85 Ethyl-[[8R-(4bS*,8α,8aβ,12bβ)- 7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinolin-12-yl] acetate hydrochlorideMe H OMe —O—

86 N-Benzyl-[[8R-(4bS*,8α,8aβ, 12bβ)-7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro[3,2-e] pyrrolo[2,3-g]isoquinolin-12-yl] acetamidehydrochloride Me H OMe —O—

87 Ethyl-[[8R-(4bS*,8α,8aβ,12bβ)- 11-diisopropylaminocarbonyl-7,10-dimethyl-1-methoxy- 5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinolin-12-yl] acetate Me H OMe —O—

88 Ethyl-[[8R-(4bS*,8α,8aβ,12bβ)- 11-isobuthylcarbonyl-7,10,12-trimethyl-1-methoxy-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline Me H OMe —O—

89 Ethyl-[[8R-(4bS*,8α,8aβ,12bβ)- 11-Diethylphosphonoyl-7,10-dimethyl-1-methoxy-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline Me H OMe —O—

90 [8R-(4bS*,8α,8aβ,12bβ)]-11- [(2,2,2-trifluoroethyl)-isopropylamino]carbonyl-7,10- dimethyl-1-methoxy-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline Me H OMe —O—

91 [8R-(4bS*,8α,8aβ,12bβ)]-10- methyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride H H OMe —O—

92 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- Dimethyl-1-hydroxy-11-(2-methylpropyl)oxycarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]- 4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride Me H OH —O—

93 [[8R-(4bS*,8α,8aβ,12bβ)]-7-Allyl- 11-(2-methylpropyl)oxycarbonyl-8a-hydroxy-10-methyl-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g](1- isoquinolinyloxy)]acetic acidAllyl OH

—O—

94 N-Methyl-[8R-(4bS*,8α,8aβ, 12bβ)]-7,10-dimethyl-1methoxy--11-(methylpropyl)oxycarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinolin-12- yl]acetamidehydrochloride Me H OMe —O—

95 N,N-Dimethyl-[8R-(4bS*,8α,8aβ, 12bβ)]-7,10-dimethyl-1methoxy--11-(methylpropyl)oxycarbonyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinolin-12-yl] acetamidehydrochloride Me H OMe —O—

96 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- dimethyl-1methoxy--11-(pyrrolidin-1-yl)carbonyl- 5,6,7,8,12,12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride MeH OMe —O—

97 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- dimethyl-1methoxy--11-(piperidin-1-yl)carbonyl-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride Me HOMe —O—

98 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- dimethyl-1methoxy--11-(morpholi-4-yl)carbonyl-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline hydrochloride Me HOMe —O—

99 [8R-(4bS*,8α,8aβ,12bβ)]-7,10- dimethyl-1-methoxy-11-(4-methyl-piperazin-1-yl)carbonyl-5,6,7,8,12, 12b-hexahydro-[9H]-4,8-methanobenzofuro[3,2-e] pyrrolo[2,3-g]isoquinoline Me H OMe —O—

100  [8R-(4bS*,8α,8aβ,12bβ)]-7,10- dimethyl-1-methoxy-11-(4-(2-hydroxyethyl)-piperazin-1-yl) carbonyl-5,6,7,8,12,12b-hexahydro-[9H]-4,8-methano benzofuro[3,2-e]pyrrolo[2,3- g]isoquinolinedihydrochloride Me H OMe —O—

101  [8R-(4bS*,8α,8aβ,12bβ)]-7,10- dimethyl-11-[N-(4-ethoxycarbonyl)phenylmethyl-N- isopropyl]aminocarbonyl-1-methoxy-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3- g]isoquinoline hydrochloride Me H OMe —O—

102  [8R-(4bS*,8α,8aβ,12bβ)]-7,10- dimethyl-1-methoxy-11-[N-(4-carboxy)phenylmethyl-N- isopropyl]aminocarbonyl-1-methoxy-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline Me H OMe —O—

103  [8R-(4bS*,8α,8aβ,12bβ)]-7,10- dimethyl-1-methoxy-11-[N-(3-ethoxycarbonyl)phenylmethyl-N- isopropyl]aminocarbonyl-1-methoxy-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3- g]isoquinoline hydrochloride Me H OMe —O—

104  [8R-(4bS*,8α,8aβ,12bβ)]-7,10- dimethyl-1-methoxy-[N-(3-carboxy)phenylmethyl-N- isopropyl]aminocarbonyl-1-methoxy-5,6,7,8,12,12b- hexahydro-[9H]-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g] isoquinoline hydrochloride Me H OMe —O—

105  [8R-(4bS*,8α,8aβ,12bβ)]-11- Methoxycarbonyl-7,10-dimethyl-1-methoxy-5,6,7,8,9,12b-hexahydro- 4,8-methanobenzofuro[3,2-e]thieno[2,3-g]isoquinoline hydrochloride Me H OMe —O—

[α]_(D) ²⁰ C = 0.1, MP Ex. R₆ R₇ R₈ MeOH (° C.) m/z NMR  1 CON(i-Pr) MeH −330.1 304 dec. 511(M+); (CDCl3); 8.46(s br, 1H); 7.31-7.14(m, 5H);CH₂Ph 363; 6.69(d, 1H); 6.62(d, 1H); 5.42(s, 1H); 4.66 336; 148; (d,1H); 4.52(d, 1H); 4.41(dq, 1H); 3.80(s, 91 3H); 3.25(dd, 1H); 3.07(d,1H); 2.61-2.47 (m, 3H); 2.47(s, 3H); 2.35(dd, 1H); 2.31 (ddd, 1H);2.05-1.89(m, 2H); 1.96(s, 3H); 1.84(dd, 1H); 1.20(d, 3H); 1.16(d, 3H).[free base]  2 CSNEt₂ Me H −313.0 >250 451 (CDCl3): 8.60(s br, 1H);6.70(d, 1H); 6.61 (M+); (d, 1H); 5.49(s, 1H); 4.00(m br, 2H); 3.80(s,436; 379; 3H); 3.79(m br, 2H); 3.24(s br, 1H); 3.08(d, 1H); 2.59-2.42(m,2H); 2.45(s, 3H); 2.39- 2.27(m, 2H); 2.00(ddd, 1H); 1.97-1.77(m, 2H);1.78(s, 3H); 1.24(t, 6H).  3 CONEt₂ Me H −151.8 217-218 407 (CDCl3):8.38(s br, 1H); 6.81(dd, 1H); 6.62 (M+); (d, 1H); 6.40(d, 1H); 4.65(d,1H); 3.60-3.40 335; 306 (m, 5H); 3.10(m, 1H); 3.00(m, 2H); 2.59- 2.32(m,3H); 2.44(s, 3H); 2.29-2.13(m, 3H); 2.05-1.80(m, 3H); 1.88(s, 3H);1.15(t, 6H)  4 CONEt₂ Me H −99.1 198-200 451 (DMSO): 11.10(s br, 1H);10.60(s, 1H); 6.95- dec. (M+); 6.85(m, 2H); 4.38(d, 1H); 3.85-3.72(m,379; 207 2H); 3.75(s, 3H); 3.68(s, 3H); 3.40-3.10(m, 7H); 2.95(m, 1H);2.79(d, 3H); 2.45-2.30 (m, 2H); 2.20-2.00(m, 2H); 1.88(m, 1H); 1.79(s,3H); 1.01(t, 6H).  5 CON(i-Pr)₂ Me H −346.5 166-168 493 (CDCl3): 8.28(sbr, 1H); 6.68(d, 1H); (M+); 6.60(d, 1H); 5.46(s, 1H); 3.89-3.79(m, 2H);393; 378; 3.80(s, 3H); 3.31(d, 1H); 3.29(d, 1H); 362 334; 3.21(s, 3H);2.69(d, 1H); 2.57(m, 1H); 149 2.51(dd, 1H); 2.42(s, 3H); 2.25(m, 1H);2.08(d, 1H); 1.92(s, 3H); 1.69-1.60(m, 2H); 1.34(d, 3H); 1.31(d, 3H).  6COOEt Me H −508.3 251 dec. 408 (CDCl3): 8.90(s br, 1H); 6.76(d, 1H);6.71 (M+); (d, 1H); 5.55(s, 1H); 4.30(q, 2H); 3.85(m, 361; 1H); 3.84(s,3H); 3.50(m br, 1H); 3.30-3.05 (m, 2H); 2.89(s, 3H); 2.88-2.60(m, 2H);2.55(dd, 1H); 2.11(s, 3H); 2.09(m, 1H); 1.83 (dd, 1H); 1.35(t, 3H).  7CONEt₂ Me H −333.4 269 dec. 477(M+); (CDCl3): 8.48(s br, 1H); 6.66(d,1H); 6.57(d, 436; 404; 1H); 5.90-5.76(m, 1H); 5.46(s, 1H); 5.28- 3635.18(m, 2H); 4.76(s br, 1H); 3.80(s, 3H); 3.60- 3.35(m, 4H);3.19-3.06(m, 4H); 2.75(dd, 1H); 2.58(m, 1H); 2.48(d, 1H); 2.35-2.25(m,3H); 1.90(s, 3H); 1.12(t, 6H).  8 CONEt₂ Me H +10.7 105-106 513(M+);(CDCl3): 7.20(dd, 2H); 7.00(s br, 1H); 6.97(d, 439, 413; 1H); 6.93(dd,1H); 6.76(d, 1H); 6.60(d, 2H); 207 4.01(d, 1H); 3.58(s, 3H); 3.43(q,4H); 3.10- 3.02(m, 2H); 2.97(dd, 1H); 2.52-2.35(m, 3H); 2.43(s, 3H);2.25(d br, 1H); 2.19(s br, 1H); 2.13(m, 1H); 1.88(s, 3H); 1.85(m, 1H);1.77(ddd, 1H); 1.14(t, 6H).  9 CONEt₂ Me H −181.5 191-192 421(M+);(CDCl3): 8.27(s br, 1H); 7.04(d, 2H); 6.81(d, 363; 349; 1H); 6.69(dd,1H); 3.73(s, 3H); 2.62-2.42(m, 290 4H); 3.39(d, 1H); 3.10(m, 1H);3.08(d, 1H); 2.85(dd, 1H); 2.66(d, 1H); 2.50(m, 1H); 2.48 (s, 3H);2.39(dd, 1H); 2.32-2.25(m, 1H); 2.20 (ddd, 1H); 2.10(dd, 1H); 1.97(ddd,1H); 1.90 (s, 3H); 1.60(d br, 1H); 1.18(t, 6H). 10 COOEt CF₃ H −456.9174 462(M+); (CDCl3): 3.25(9.40(s br, 1H); 6.69(d, 1H); 415; 372 6.66(d,1H); 5.40(s, 1H); 4.34(q, 2H); 3.81(s, 3H); dd, 1H); 3.06(d, 1H);2.73(m, 1H); 2.60- 2.42(m, 3H); 2.44(s, 3H); 2.31(ddd, 1H); 2.05-1.86(m, 3H); 1.35(t, 3H) 11 COOEt i-Pr H −409.7 221-223 436(M+) (CDCl3):8.88(s br, 1H); 6.70(d, 1H); 6.62 dec. (d, 1H); 5.40(s, 1H);4.32-4.22(m, 2H); 3.81(s, 3H); 3.61(dq, 1H); 3.22(dd, 1H); 3.06(m, 1H);2.63-2.41(m, 5H); 2.41(s, 3H); 2.31(ddd, 1H); 2.02-1.87(m, 3H); 1.34(t,3H); 1.19(d, 3H); 1.17(d, 3H). 12 CONEt₂ Me H −466.9 213 421(M+);(CDCl3): 8.40(s br, 2H); 6.70(d, 1H); 6.60 348; 322 (d, 1H); 5.41(s,1H); 3.80(s, 3H); 3.52- 3.40(m, 5H); 3.09(dd, 1H); 2.85(m, 2H); 2.80(d,1H); 2.41-2.30(m, 2H); 1.96- 1.70(m, 3H); 1.39(s, 3H); 1.18(t, 6H); 13COPh Me H −622.2 184-187 440(M+); (CDCl3): 8.91(s br, 1H); 7.62(d, 2H);7.51 dec 382; 241; (dd, 1H); 7.43(dd, 2H); 6.69(d, 1H); 6.62 105 (d,1H); 5.45(s, 1H); 3.80(s, 3H); 3.27(dd, 1H); 3.07(d, 1H); 2.62-2.38(m,4H); 2.45 (s, 3H); 2.32(ddd, 1H); 2.02(ddd, 1H); 1.92 (ddd, 1H); 1.88(s,3H); 1.85(dd, 1H). 14 COOH Me H −599.0 205-208 380(M+); (CDCl3+TFA);9.60(s br, 1H); 6.81(d, 336 1H); 6.79(d, 1H); 5.60(s, 1H); 4.19(s br,1H); 3.85(s, 3H); 3.55(d br, 1H); 3.18(m, 2H); 3.02-2.80(m, 5H);2.58(dd, 1H); 2.48 (ddd, 1H); 2.19(dd, 1H); 2.15(s, 3H); 1.85 (dd, 1H)15 CONEt₂ Me H −411.9 228-229 525(M+); (CDCl3): 8.40(s br, 1H);7.32-7.18(m, 5H); 434; 361 6.68(d, 1H); 6.60(d, 1H); 5.46(s, 1H);3.52-3.40(m, 4H); 3.38(dd, 1H); 3.01(d, 1H); 2.87-2.69(m, 5H);2.59-2.45(m, 2H); 2.40-2.30(m, 2H); 2.00(ddd, 1H); 1.90 (ddd, 1H);1.89(s, 3H); 1.82(dd, 1H); 1.15 (t, 6H). 16 CONEt₂ Me H −294.8 195-197449(M+); (CDCl3): 8.40(s br, 1H); 6.63(d, 1H); 6.58 434; 375; (d, 1H);5.44(s, 1H); 3.80(s, 3H); 3.55-3.38 361 (m, 4H); 3.36(dd, 1H); 2.98(d,1H); 2.67 (ddd, 1H); 2.60(q, 2H); 2.56-2.43(m, 2H); 2.36(dd, 1H);2.25(ddd, 1H); 1.98(ddd, 1H); 1.97-1.85(m, 1H); 1.89(s, 3H); 1.81 (dd,1H); 1.15(t, 3H). 17 COMe Me H −615.0 115-140 378(M+) (CDCl3): 9.07(sbr, 2H); 6.70(d, 1H); 6.60(d, 1H); 5.40 (s, 1H); 3.80(s, 3H); 3.25(dd,1H); 3.06(d, 2H); 2.60- 2.40(m, 4H); 2.45(s, 3H); 2.40(s, 3H); 2.32(ddd,1H); 2.15(s, 3H); 2.00(ddd, 1H); 1.91(ddd, 1H); 1.83(dd, 1H) 18 CO(i-Bu)Me H −497.1 221-225 420(M+) CDCl3(free base): 9.10(s br, 1H); 6.659d,1H); 6.60(d, 1H); 5.41(s, 1H); 3.79(s, 3H); 3.24(dd, 1H); 3.06(d, 1H);2.60- 2.37(m, 4H); 2.55(dd, 2H); 2.44(s, 3H); 2.31(ddd, 1H); 2.22(dq,1H); 2.14(s, 3H); 1.99(ddd, 1H); 1.90(ddd, 1H); 1.82(dd, 1H); 0.98(d,3H); 0.97(d, 3H). 19 CONEt₂ Me H −475.2 257 dec. 511(M+); CDCl3: 8.36(sbr, 1H); 7.40-7.22(m, 5H); 6.68(d, 1H); 438; 347; 6.62(d, 1H); 5.43(s,1H); 3.80(s, 3H); 3.71(q, 2H); 3.55- 91 3.35(m, 5H); 3.25(dd, 1H);3.09(d, 1H); 2.61-2.49(m, 2H); 2.38(ddd, 1H); 2.30(dd, 1H); 1.99(ddd,1H); 1.90- 1.85(m, 1H); 1.88(s, 3H); 1.79(dd, 1H); 1.11(t, 6H). 20CONEt₂ Me H −373.7 160-162 463(M+); CDCl3: 836(s br, 1H); 6.66(d, 1H);6.54(d, 1H); 448; 375 5.43(s, 1H); 3.80(s, 3H); 3.59(dd, 1H);3.55-3.38(m, 4H); 2.95(d, 1H); 2.89(ddd, 1H); 2.71(dq, 1H); 2.56(dd,1H); 2.45(m, 1H); 2.34(dd, 1H); 2.21(ddd, 1H); 1.95- 1.88(m, 2H);1.89(s, 3H); 1.80(dd, 1H); 1.17- 1.10(m, 12H). 21 CONEt₂ Me H −373.4 229dec. 463(M+); CDCl3(free base): 8.42(s br, 1H); 6.68(d, 1H); 434; 361;6.59(d, 1H); 5.45(s, 1H); 3.79(s, 3H); 3.56-3.39(m, 4H); 210; 583.31(dd, 1H); 2.99(d, 1H); 2.63(dd, 1H); 2.56-2.41(m, 4H); 2.35(dd, 1H);2.29(ddd, 1H); 1.98(ddd, 1H); 1.90(m, 1H); 1.90(s, 3H); 1.81(dd, 1H);1.59-1.47(m, 2H); 22 CON(i-Pr)₂ Me H −312.8 215 dec. 477(M+); CDCl3(freebase): 8.29(s br, 1H); 6.66(d, 1H); 376; 6.59(d, 1H); 5.41(s, 1H);4.10-3.99(m, 2H); 3.88- 350; 100 3.78(m, 2H); 3.21(dd, 1H); 3.04(d, 1H);2.59-2.42(m, 3H); 2.43(s, 3H); 2.39-2.25(m, 2H); 1.98(ddd, 1H); 1.89(m,1H); 1.89(s, 3H); 1.81(dd, 1H); 1.38- 1.31(m, 15H). 23 CON(i-Pr)₂ Me H−299.1 220-225 491(M+); CDCl3(free base): 8.27(s br, 1H); 6.66(d, 1H);6.58(d, 1H); 449; 391; 5.49(s, 1H); 4.52(dq, 1H); 3.80(dq, 2H); 3.22(dd,1H); 364; 347; 3.02(d, 1H); 2.59-2.41(m, 3H); 2.42(s, 3H); 2.32(dd, 1H);321 2.30(ddd, 1H); 1.98(ddd, 1H); 1.91-1.85(m, 1H); 1.87(s, 3H);1.83(dd, 1H); 1.35(d, 6H); 24 CON(i-Pr)₂ CF₃ H −300.6 219-221 517(M+);CDCl3: 9.00(s br, 1H); 6.69(d, 1H); 6.62(d, 1H); dec. 416; 388; 5.39(s,1H); 3.79(s, 3H); 3.69-3.55(m br, 2H); 200; 3.23(dd, 1H); 3.04(d, 1H);2.52-2.45(m, 4H); 2.43(s, 3H); 2.30(ddd, 1H); 2.00-1.90(m, 2H);1.88(ddd, 1H); 1.30(m br, 12H). 25 CO-i-Bu Me H −463.3 198-201 462(M+);CDCl3(free base): 9.12(s br, 1H); 6.68(d, 1H); 421 6.61(d, 1H);5.84(ddt, 1H); 5.42(s, 1H); 5.52(d, 1H); 5.18(d, 1H); 4.74(s br, 1H);3.80(s, 3H); 3.20-3.08(m, 4H); 2.76(dd, 1H); 2.61-2.47(m, 4H);2.34-2.19(m, 4H); 2.17(s, 3H); 1.79-1.69(m, 1H); 0.96(d, 6H). 26 CO-i-BuMe H −478.3 245-250 448(M+); CDCl3(base): 9.30(s br, 1H); 6.66(d, 1H);6.56(d, 1H); 407 5.84(ddt, 1H); 5.46(s, 1H); 5.22(d, 1H); 5.19(d, 1H);4.08(s br, 1H); 3.17(d, 2H); 3.14(d, 1H); 3.10(d, 1H); 2.73(dd, 1H);2.61(m, 1H); 2.58 and 2.54(ABX, 2H); 2.49(d, 1H); 2.37-2.27(m, 2H);2.30(d, 1H); 27 CO-i-Bu Me H −471.1 259-262 476(M+); CDCl3(base): 8.12(sbr, 1H); 6.66(d, 1H); 6.58(d, 1H); dec. 435 5.84(ddt, 1H); 5.54(s, 1H);5.22(d, 1H); 5.19(d, 1H); 4.47(s br, 1H); 4.11-3.96(m, 2H); 3.16(d, 2H);3.15(d, 1H); 3.10(d, 1H); 2.75(dd, 1H); 2.62-2.50(m, 3H); 2.50(d, 1H);2.29(d, 1H); 2.29-2.20(m, 3H); 28 CON(iPr)₂ Me H −378.0 214-244 461(M+);CDCl3(base): 8.27(s br, 1H); 6.86(d, 1H); 6.60(d, 1H); 418; 361; 5.39(s,1H); 3.87-3.72(m, 2H); 3.22(dd, 1H); 3.06(d, 1H); 334 2.59-2.48(m, 5H);2.42(s, 3H); 2.39-2.28(m, 2H); 1.99(ddd, 1H); 1.88(s, 3H); 1.88(m, 1H);1.80(dd, 1H); 1.31(d, 6H); 1.29(d, 6H); 1.11(t, 3H). 29

Me H −627.5 169-171 418(M+) CDCl3: 8.91(s br, 1H); 6.68(d, 1H); 6.64(d,1H); 5.48(s, 1H); 3.79(s, 3H); 3.28(dd, 1H); 3.08(d, 1H); 2.60- 2.28(m,5H); 2.46(s, 3H); 2.39(s, 3H); 2.01(s, 3H); 2.01(ddd, 1H); 1.92(ddd,1H); 1.88(dd, 1H). 30 CON(i-Pr)₂ Me H −436.0 >300 527(M+); CDCl3(freebase): 8.30(s br, 1H); 7.20(d, 1H); 427; 400; 6.44(d, 1H); 5.40(s, 1H);4.81(s br, 1H); 3.90- 100 3.80(m, 2H); 3.11(d, 1H); 3.01(d, 1H);2.68(dd, 1H); 2.50(m, 1H); 2.43(s, 3H); 2.39-2.19(m, 4H); 1.91(s, 3H);1.69(dd, 1H); 1.33(d, 12H). 31 COOEt CH₃ H −393 212-216 480(M+);CDCl3(free base): 9.03(s br, 1H); 6.66(d, 1H); COOEt 451; 407; 6.61(d,1H); 5.45(s, 1H); 4.28(q, 2H); 4.08(q, 2H); 393; 3.80(s, 3H); 3.73(d,1H); 3.61(d, 1H); 3.22(dd, 1H); 281; 200 3.04(d, 1H); 2.60-2.42(m, 3H);2.42(s, 3H); 2.40(dd, 1H); 2.31(ddd, 1H); 1.99(ddd, 1H); 1.89(ddd, 1H);32 CO-t-Bu Me H −453.7 249-252 420(M+); CDCl3(free base): 8.77(s br,1H); 6.66(d, 1H); dec. 405; 363; 6.62(d, 1H); 5.45(s, 1H); 3.80(s, 3H);3.25(dd, 1H); 320; 57 3.06(d, 1H); 2.60-2.40(m, 4H); 2.44(s, 3H);2.31(ddd, 1H); 2.17(s, 3H); 2.00(ddd, 1H); 1.91(ddd, 1H); 1.82(dd, 1H);1.32(s, 9H). 33 CON(i-Pr)₂ Me H −499.0 280-283 511(M+) CDCl3: 8.34(s br,1H); 7.20(d, 1H); 6.45(d, 1H); 411; 5.40(s, 1H); 3.88-3.75(m, 2H);3.30(dd, 1H); 2.97(d, 1H); 384; 2.60-2.43(m, 3H); 2.45(s, 3H); 2.35(dd,1H); 100 2.25(ddd, 1H); 1.98(ddd, 1H); 1.89(s, 3H); 1.87(ddd, 1H);1.78(dd, 1H); 1.31(d, 6H); 1.29(d, 6H). 34 CO-i-Pr Me H −495.6 267-269406(M+); CDCl3(free base): 9.18(s br, 1H); 6.68(d, 1H); 391; 207;6.61(d, 1H); 5.41(s, 1H); 3.98(s, 3H); 3.25(dd, 1H); 3.21- 200 3.11(m,1H); 3.06(d, 1H); 2.60-2.39(m, 4H); 2.44(s, 3H); 2.31(ddd, 1H); 2.18(s,3H); 1.99(ddd, 1H); 1.91(ddd, 1H); 1.83(dd, 1H); 1.16(d, 3H); 1.11(d,3H). 35 CO-i-Bu Me H −693 300-303 468(M+); CDCl3(free base): 9.12(s br,1H); 7.10(d, 1H); 411; 6.48(d, 1H); 5.39(s, 1H); 3.32(dd, 1H); 2.98(d,1H); 2.59 283; 57 and 2.54(ABX, 2H); 2.59-2.37(m, 4H); 2.45(s, 3H);2.23(ddd, 1H); 2.22(m, 1H); 2.16(s, 3H); 1.99(ddd, 1H); 1.89(ddd, 1H);1.78(dd, 1H); 0.99(d, 3H); 0.98(d, 3H). 36 CON(i-Pr)₂ Me H −226 222-225419(M+); CDCl3: 8.00(s br, 1H); 7.22(m, 1H); 7.10(m, 3H); 3.90- 376;319; 3.81(m, 2H); 3.48(d, 1H); 3.11(d, 1H); 3.09(dd, 1H); 292; 1002.89(dd, 1H); 2.61(d, 1H); 2.46(ddd, 1H); 2.45(s, 3H); 2.35(dd, 1H);2.27(m, 1H); 2.15(ddd, 1H); 2.05(m, 2H); 1.94(ddd, 1H); 1.84(s, 3H); 37COO-i-Pr Me H −449 225-227 422(M+); CDCl3(free base): 8.90(s br, 1H);6.65(d, 1H); dec. 379; 361; 6.00(d, 1H); 5.41(s, 1H); 5.11(m, 1H);3.79(s, 3H); 200 3.23(dd, 1H); 3.04(d, 1H); 2.59-2.43(m, 3H); 2.43(s,3H); 2.40(dd, 1H); 2.30(ddd, 1H); 2.12(s, 3H); 1.99(ddd, 1H); 1.90(ddd,1H); 1.82(dd, 1H); 1.31(d, 3H); 1.29(d, 3H). 38 COO-t-Bu Me H −487257-260 436(M+); CDCl3(free base): 8.81(s br, 1H); 6.69(d, 1H); dec.379; 363; 6.61(d, 1H); 5.37(s, 1H); 3.80(s, 3H); 3.24(dd, 1H); 243; 2003.05(d, 1H); 2.59-2.44(m, 3H); 2.44(s, 3H); 2.40(dd, 1H); 2.31(ddd, 1H);2.11(s, 3H); 1.99(ddd, 1H); 1.90(ddd, 1H); 1.82(dd, 1H); 1.53(s, 9H). 39COOMe Me H −474.4 232-235 394(M+); CDCl3(free base): 8.90(s br, 1H);6.68(d, 1H); dec. 361; 200 6.62(d, 1H); 5.46(s, 1H); 3.80(s, 3H);3.79(s, 3H); 3.24(dd, 1H); 3.06(d, 1H); 2.59-2.45(m, 3H); 2.45(s, 3H);2.40(dd, 1H); 2.31(ddd, 1H); 2.12(s, 3H); 1.99(ddd, 1H); 1.90(ddd, 1H);1.82(d, 1H). 40 COO-n-Pr Me H −462.2 230-232 422(M+); CDCl3(free base):8.90(s br, 1H); 6.66(d, 1H); dec. 405; 361; 6.60(d, 1H); 5.40(s, 1H);4.20(t, 2H); 3.80(s, 3H); 285; 200 3.24(dd, 1H); 3.05(d, 1H);2.59-2.43(m, 3H); 2.43(s, 3H); 2.40(dd, 1H); 2.31(ddd, 1H); 2.13(s, 3H);1.99(ddd, 1H); 1.90(ddd, 1H); 1.82(dd, 1H); 1.79-1.66(m, 2H); 1.00(t,3H). 41 CO-i-Bu Me H −449.7 291-294 432(M+) CDCl3(free base): 9.25(s br,1H); 7.61(d, 1H); dec. 6.74(d, 1H); 5.55(s, 1H); 3.27(dd, 1H); 3.10(d,1H); 2.61- 2.51(m, 4H); 2.52(s, 3H); 2.46-2.40(m, 1H); 2.44(s, 3H);2.30-2.13(m, 3H); 2.17(s, 3H); 2.02(ddd, 1H); 1.89(ddd, 1H); 1.79(dd,1H); 0.98(d, 6H). 42 COCOOEt Me H −365.0 190 dec. 436(M+); CDCl3(freebase): 9.50(s br, 1H); 6.78(d, 1H); 407; 362; 6.70(d, 1H); 5.52(s, 1H);4.28(q, 2H); 3.80(s, 3H); 191 3.54(m, 1H); 3.28(m, 1H); 3.10-2.98(m,3H); 2.88(s, 3H); 2.68(m, 2H); 2.60(s, 3H); 2.10-2.00(m, 3H); 1.40(t,3H). 43 CO-i-Bu Me H −195 215 dec. 422(M+); CDCl3(free base): 8.70(s br,1H); 6.68(d, 1H); 379; 285; 6.61(d, 1H); 5.93(s, 1H); 4.62(d, 1H);3.80(s, 3H); 192 3.06(m, 1H); 3.00(d, 1H); 2.88(dd, 1H); 2.60-2.40(m,5H); 2.41(s, 3H); 2.25-2.10(m, 4H); 2.13(s, 3H); 1.96(ddd, 1H);1.81(ddd, 1H); 0.96(d, 3H); 0.94(d, 3H). 44 CO-i-Bu Me H −177.3 208 dec.464(M+); CDCl3(free base): 8.80(s br, 1H); 6.62(d, 1H); 254 6.58(d, 1H);5.98(s, 1H); 5.83(ddt, 1H); 5.20(d, 1H); 5.15(d, 1H); 4.45(s br, 1H);4.41(d, 1H); 3.79(s, 3H); 3.15- 3.00(m, 5H); 2.85(d, 1H); 2.60-2.50(m,3H); 2.48- 2.35(m, 2H); 2.22-2.00(m, 3H); 2.10(s, 3H); 1.68(m, 1H);0.96(d, 3H); 0.94(d, 3H) 45 CO-i-Bu Me H −476.6 205-209 446(M+)CDCl3(free base): 9.10(s br, 1H); 6.67(d, 1H); 6.60(d, 1H); 5.89(ddt,1H); 5.41(s, 1H); 5.22(d, 1H); 5.15(d, 1H); 3.80(s, 3H); 3.36(dd, 1H);3.27-3.12(m, 2H); 3.00(d, 1H); 2.65(dd, 1H); 2.56(d, 2H); 2.56-2.35(m,2H); 2.35-2.11(m, 3H); 2.15(s, 3H); 1.98(ddd, 1H); 1.90(ddd, 1H);1.80(dd, 1H); 0.98(d, 6H) 46 CON(i-Pr)₂ Me H −93.2 190-195 507(M+);CDCl3: 8.20(s br, 1H); 6.95(d, 1H); 6.75(d, 1H); 464; 407; 4.00(d, 1H);3.91-3.82(m, 2H); 3.70(s, 3H); 3.29(m, 1H); 380; 365; 3.10(dd, 1H);3.00(d, 1H); 2.68(dd, 1H); 2.55(d, 1H); 2.49(s, 3H); 2.43-2.11(m, 4H);2.29(s, 3H); 1.92(ddd, 1H); 1.88(s, 3H); 1.74(d br, 1H); 1.32(d, 12H).47 CO-i-Bu Me H 185.8 216-220 462 CDCl3(free base): 8.86(s br, 1H);6.60(m, 2H); 5.82(d, 1H); (M+); 5.82(ddt, 1H); 5.72(d, 1H); 5.20(d, 1H);5.06(d, 1H); 4.41(s 378; br, 1H); 3.83(d, 1H); 3.18-3.09(m, 3H);3.05-2.92(m, 2H); 252 2.81(d, 1H); 2.60-2.30(m, 6H); 2.28-2.02(m, 2H);2.11(s, 3H); 1.51(m, 1H); 0.96(d, 6H). 48 CO-3-pentyl Me H −598.7260-262 434 CDCl3(free base): 9.16(s br, 1H); 6.69(d, 1H); 6.60(d, 1H);dec. (M+); 5.42(s, 1H); 3.80(s, 3H); 3.25(dd, 1H); 3.08(d, 1H); 417;2.93(m, 1H); 2.60-2.40(m, 4H); 2.43(s, 3H); 2.31(ddd, 1H); 235 2.19(s,3H); 1.99(ddd, 1H); 1.90(ddd, 1H); 1.83(dd, 1H); 1.74(dq, 2H); 1.50(dq,2H); 49 CO-i-Pr Me H −569.5 240-243 420 CDCl3(free base): 6.68(d, 1H);6.61(d, 1H); 5.50(s, 1H); (M+); 3.91(s, 3H); 3.81(s, 3H); 3.28-3.18(m,2H); 3.06(d, 1H); 405; 2.60-2.42(m, 3H); 2.43(s, 3H); 2.41(dd, 1H);2.32(ddd, 1H); 377 2.13(s, 3H); 1.99(ddd, 1H); 1.92(ddd, 1H); 1.82(dd,1H); 1.15(d, 3H); 1.12(d, 3H). 50 CON(i-Pr)₂ Me H −353.7 209-210 479CDCl3(free base): 8.28(s br, 1H); 6.67(d, 1H); 6.59(d, 1H); (M+);5.43(s, 1H); 5.58(s br, 1H); 3.90-3.79(m, 2H); 3.79(s, 3H); 379; 3.20(d,1H); 2.94(d, 1H); 2.72(dd, 1H); 2.47(d, 1H); 352 2.45(m, 2H); 2.41(s,3H); 2.41(d, 1H); 2.30(m, 1H); 1.91(s, 3H); 1.72(m, 1H); 1.32(d, 6H);1.30(d, 6H). 51 Me Me H −305.5 132-136 350 CDCl3: 7.70(s br, 1H);6.67(d, 1H); 6.60(d, 1H); (M+) 5.49(s, 1H); 3.80(s, 3H); 3.40(m, 1H);3.05(d, 1H); 2.70- 2.55(m, 3H); 2.50(s, 3H); 2.40(m, 1H); 2.34(m, 1H);2.10(s, 3H); 2.02(m, 1H); 1.89(ddd, 1H); 1.79(dd, 1H); 1.78(s, 3H). 52CON(i-Pr)₂ Me H −182.2 204-207 513 CDCl3: 8.55(s br, 1H); 6.97(d, 1H);6.22(d, 1H); (M+); 4.68(d, 1H); 3.89-3.80(m, 2H); 3.06(dd, 1H); 2.81(d,1H); 470; 2.71(dd, 1H); 2.50-2.30(m, 3H); 2.38(s, 3H); 2.20- 433.1.95(m, 5H); 1.81(s, 3H); 1.72(ddd, 1H); 1.25(d, 12H). 53

Me H −383.9 247-250 470 (M+); 361; 200; 91 CDCl3(free base): 8.90(s br,1H); 7.41-7.31(m, 5H); 6.66(d, 1H); 6.61(d, 1H); 5.40(s, 1H); 5.26(s,2H); 3.80(s, 3H); 3.22(dd, 1H); 3.05(d, 1H); 2.59-2.45(m, 3H); 2.42(s,3H); 2.40(dd, 1H); 2.30(ddd, 1H); 2.14(s, 3H); 1.99(ddd, 1H); 1.89(ddd,1H); 1.81(dd, 1H). 54 CON(i-Pr)₂ Me H −402.8 219-220 489 CDCl3: 8.22(sbr, 1H); 6.68(d, 1H); 6.60(d, 1H); (M+); 5.89(ddt, 1H); 5.43(s, 1H);5.24(d, 1H); 5.15(d, 1H); 3.85- 388; 3.76(m, 2H); 3.80(s, 3H); 3.34(dd,1H); 3.25-3.12(m, 2H); 361; 347 2.99(d, 1H); 2.62(ddd, 1H); 2.50(dd,1H); 2.49(m, 1H); 2.34(dd, 1H); 2.29(ddd, 1H); 1.98(ddd, 1H); 1.89(m,1H); 1.89(s, 3H); 1.80(dd, 1H); 1.33(d, 6H); 1.31(d, 6H). 55 COO-i-Bu MeH −153 265-266 438 CDCl3(free base): 8.48(s br, 1H); 6.61(d, 1H);6.59(d, 1H); (M+); 5.71(s br, 1H); 4.61(d, 1H); 3.99(d, 2H); 3.79(s,3H); 301 3.04(dd, 1H); 3.00(d, 1H); 2.39(dd, 1H); 2.41-2.36(m, 3H);2.41(s, 3H); 2.25-2.10(m, 3H); 2.11(s, 3H); 2.05-1.90(m, 2H); 1.81(ddd,1H); 0.92(d, 6H). 56 CON(i-Pr)₂ Me H −388 254-156 493 CDCl3: 8.25(s br,1H); 6.68(d, 1H); 6.60(d, 1H); 5.45(s, 1H); (M+); 3.86-3.75(m, 2H);3.79(s, 3H); 3.59(m, 2H); 3.24(dd, 1H); 462; 361 2.95(d, 1H); 2.80(m,1H); 2.73-2.61(m, 4H); 2.50(m, 1H); 2.45-2.31(m, 2H); 1.95-1.88(m, 2H);1.88(s, 3H); 1.80(dd, 1H); 1.31(d, 6H); 1.29(d, 6H). 57 CONH₂ Me H−463.2 279-281 379 CDCl3(free base: 9.42(s br, 1H); 6.62(d, 1H); (M+);6.58(d, 1H); 5.63(s br, 2H); 5.48(s, 1H); 362; 347 3.80(s, 3H); 3.24(dd,1H); 3.06(d, 1H); 2.59- 2.42(m, 3H); 2.42(s, 3H); 2.40(dd, 1H);2.31(ddd, 1H); 2.11(s, 3H); 1.99(ddd, 1H); 1.91(ddd, 1H); 1.84(dd, 1H).58

Me H −316.3 219-221 527 (M+); 252; 148; 106; 91 CDCl3(free base): 8.50(sbr, 1H); 7.28-7.15(m, 5H); 6.66(d, 1H); 6.60(d, 1H); 5.41(s, 1H);4.63(d, 1H); 4.51(d, 1H); 4.41(dq, 1H); 3.78(s, 3H); 3.20(d, 1H);2.94(d, 1H); 2.73(dd, 1H); 2.50-2.44(m, 2H); 2.41(s, 3H); 2.37-2.27(m,3H); 1.98(s, 3H); 1.77-1.67(m, 2H); 1.16(d, 6H). 59

Me H −161.3 238-242 467 (M+); 381; 336; 85; 72 CDCl3(free base): 8.77(sbr, 1H); 6.61(d, 1H); 6.59(d, 1H); 5.93(s br, 1H); 4.61(d, 1H); 4.30(m,2H); 3.80(s, 3H); 3.05(m, 1H); 2.97-2.89(m, 4H); 2.83(dq, 1H); 2.52-2.38(m, 3H); 2.41(s, 3H); 2.23-2.13(m, 3H); 2.11(s, 3H); 1.95(m, 1H);1.81(ddd, 1H); 1.01(d, 6H). 60 COOCH₂Ph Me H −399.2 206-210 470CDCl3(free base): 8.90(s br, 1H); 7.41-7.31(m, 5H); (M+); 6.66(d, 1H);6.61(d, 1H); 5.40(s, 1H); 5.26(s, 2H); 361; 3.80(s, 3H); 3.22(dd,, 1H);3.05(d, 1H); 2.59-2.45(m, 3H); 200; 91 2.42(s, 3H); 2.40(dd, 1H);2.30(ddd, 1H); 2.14(s, 3H); 1.99(ddd, 1H); 1.89(ddd, 1H); 1.81(dd, 1H).61 COO-i-Bu Me H −428.78 285-288 448 CDCl3(free base): 9.00(s br, 1H);7.63(d, 1H); 6.75(d, 1H); (M+); 5.58(s, 1H); 4.04(ABX, 2H); 3.27(dd,1H); 3.10(d, 1H); 391; 373 2.60-2.51(m, 3H); 2.53(s, 3H); 2.45(s, 3H);2.43(dd, 1H); 2.25(ddd, 1H); 2.14(s, 3H); 2.09-1.95(m, 2H); 1.89(ddd,1H); 1.79(dd, 1H); 1.00(d, 6H). 62 CON(i-Pr)₂ Me H −384.1 279-280 477CDCl3(free base): 6.68(d, 1H); 6.59(d, 1H); 5.50(s, 1H); (M+); 3.80(s,3H); 3.70(s br, 2H); 3.60(s, 3H); 3.20(dd, 1H); 377; 349 3.03(d, 1H);2.59-2.42(m, 3H); 2.42(s, 3H); 2.36- 2.27(m, 2H); 1.99(ddd, 1H);1.90(ddd, 1H); 1.82(dd, 1H); 1.80(s, 3H); 1.32(s br, 12H). 63

Me H −150.3 218-220 478 (M+); 461; 379; 363. CDCl3(free base): 8.90(sbr, 1H); 5.68(d, 1H); 6.61(d, 1H); 5.45(s, 1H); 4.78(dd, 1H); 3.80(s,3H); 3.25(dd, 1H); 3.07(d, 1H); 2.59-2.42(m, 3H); 3.42(s, 3H); 2.41(dd,1H); 2.31(ddd, 1H); 2.15(s, 3H); 2.03-1.91(m, 4H); 1.85(dd, 1H); 0.91(d,6H); 0.89(d, 1H). 64 COO-i-Bu Me H −665.2 211-214 484 CDCl3: 8.84(s br,1H); 7.20(d, 1H); 6.48(d, 1H); 5.40(s, 1H); (M+); 4.04(ABX, 2H);3.32(dd, 1H); 2.98(d, 1H); 2.61- 411; 2.48(m, 3H); 2.48(s, 3H); 2.41(dd,1H); 2.25(ddd, 1H); 299; 2.13(s, 3H); 2.09-1.91(m, 2H); 1.89(ddd, 1H);1.79(dd, 1H); 158. 0.99(d, 6H). 65 COO-i-Bu Me H −260.2 231-236 392CDCl3(free base): 8.50(s br, 1H); 7.20(m, 1H); 7.09(m, 3H); (M+);3.99(d, 2H); 3.42(d, 1H); 3.12(d, 1H); 3.11(dd, 1H); 208; 2.39(dd, 1H);2.63(d, 1H); 2.51-2.46(m, 1H); 2.46(s, 3H); 184; 2.41(dd, 1H); 2.29(m,1H); 2.15(ddd, 1H); 2.11-1.91(m, 3H); 173. 2.08(s, 3H); 1.59(m, 1H);0.98(d, 6H). 66 CON(i-Pr)₂ Me H −345.5 117-121 535 CDCl3: 8.20(s br,1H); 6.67(d, 1H); 6.60(d, 1H); 5.42(s, 1H); (M+); 4.20(q, 2H); 3.81(m,2H); 3.80(s, 3H); 3.42(d, 1H0; 462; 3.37(dd, 1H); 3.31(d, 1H); 2.94(d,1H); 2.71(dd, 1H); 2.67- 361 2.58(m, 2H); 2.40(ddd, 1H); 2.34(dd, 1H);2.06(ddd, 1H); 1.89(s, 3H); 1.88(m, 1H); 1.79(dd, 1H); 1.34(d, 6H);1.32(d, 6H); 1.29(t, 3H). 67 CON(i-Pr)₂ Me H −321.9 240-244 507 (DMSO):6.90(d, 1H); 6.87(d, 1H); 5.79(s, 1H); 4.28(m, 1H); (M+) 4.12-3.98(m,2H); 3.79(s, 3H); 3.79-3.65(m, 2H); 3.57(m, 1H); 3.40-3.22(m, 2H);3.05(m, 1H); 2.90(m, 1H); 2.60(m, 1H); 2.39(ddd, 1H); 2.20(m, 1H);1.88-1.80(m, 1H); 1.85(s, 3H); 1.23(m, 12H). 68 CONMe₂ Me H −363.3228-229 407 CDCl3: 8.58(s br, 1H); 6.66(d, 1H); 6.61(d, 1H); dec. (M+);5.44(s, 1H); 3.80(s, 3H); 3.22(dd, 1H); 3.06(d, 1H); 3.02(s, 6H);2.59-2.44(m, 3H); 2.44(s, 3H); 2.34(dd, 1H); 2.31(ddd, 1H); 1.99(ddd,1H); 1.91(s, 3H); 1.90(ddd, 1H); 1.82(dd, 1H). 69 COO-i-Bu Me H 184.5297-298 422 CDCl3(base): 8.48(s br, 1H); 7.01(d, 1H); 6.72(d, 1H); dec.(M+); 6.65(dd, 1H); 3.99(d, 2H); 3.71(s, 3H); 3.35(d, 1H); 363; 3.10(dd,1H); 3.08(d, 1H); 2.81(dd, 1H); 2.62(d, 1H); 349; 2.49(m, 1H); 2.44(s,3H); 2.41(dd, 1H); 2.25(m, 1H); 2.18- 214 1.90(m, 4H); 2.09(s, 3H);1.59(m, 1H); 0.92(d, 6H). 70 CON(i-Pr)₂ Me H −335.5 172-177 449 CDCl3:8.30(s br, 1H); 6.70(d, 1H); 6.61(d, 1H); (M+); 5.40(s, 1H);3.89-3.79(m, 1H); 3.80(s, 3H); 2.61- 406; 2.49(m, 1H); 3.09(dd, 1H);2.85(m, 1H); 2.82(d, 1H); 349; 2.50-2.42(m, 1H); 2.35(dd, 1H);1.95-1.70(m, 6H); 322. 1.88(s, 3H); 1.32(d, 6H); 1.30(d, 6H). 71 COOHCH₃ H −357.7 235 dec. 425 DMSO(disodium salt): 10.93(s br, 1H); 6.66(d,1H); COOH (MH+); 6.59(d, 1H); 5.36(s, 1H); 3.58(s, 3H); 3.45(m, 1H);407. 3.15(m, 3H); 2.93(d, 1H); 2.49-2.39(m, 1H); 2.38- [FAB 2.24(m, 2H);2.30(s, 3H); 2.12(ddd, 1H); 1.90(ddd, 1H); POS] 1.70-1.59(m, 2H). 72CON(i-Pr)₂ Me H −357.7 282-286 506 CDCl3: 8.30(s br, 1H); 6.74(d, 1H);6.68(d, 1H); (M+); 5.50(s, 1H); 3.90-3.80(m, 2H); 3.84(s, 3H); 3.32(d,1H); 462; 3.31(m, 1H); 3.12(d, 1H); 2.95(d, 1H); 2.77(dd, 1H); 2.70-369; 2.60(m, 1H); 2.60-2.50(m, 2H); 2.40(dd, 1H); 2.00- 361. 1.92(m,2H); 1.92(s, 3H); 1.85(dd, 1H); 1.37(d, 6H); 1.35(d, 6H). 73 CSN(i-Pr)₂Me H −364.9 296 dec. 479 CDCl3: 8.20(s br, 1H); 6.73(d, 1H); 6.68(d,1H); (M+); 5.50(s, 1H); 4.30(m, 2H); 3.88(m, 1H); 3.80(s, 3H); 436;3.24(m, 2H); 3.08(m, 2H); 2.92-2.70(m, 1H); 2.88(s, 3H); 379; 33 2.50(m,1H); 2.44(dd, 1H); 2.08(dd, 1H); 1.81(dd, 1H); 1.81(s, 3H); 1.45(s br,12H). 74 COO-i-Bu Me H −465.4 270-272 494 DMSO: 12.10(s br, 1H); 6.79(d,1H); 6.71(d, 1H); dec. (M+); 5.72(s, 1H); 5.08(d, 1H); 4.92(d, 1H);3.92(ABX, 2H); 450; 3.85(m, 1H); 3.70(s, 3H); 3.21(d, 1H); 3.08-2.80(m,3H); 437; 2.78(s, 3H); 2.62(m, 1H); 2.45(dd, 1H); 2.23(ddd, 1H); 393;2.09(s, 3H); 2.00-1.88(m, 2H); 1.69(dd, 1H); 295. 0.91(d, 6H). 75CON(i-Pr)₂ Me H −221.4 180-184 435 CDCl3: 8.04(s br, 1H); 7.20(m, 1H);7.05(m, 3H); 4.58(s (M+); br, 1H); 3.95-3.81(m, 2H); 3.23(d, 1H);3.15(d, 1H); 335; 3.00(dd, 1H); 2.93-2.88(m, 2H); 2.45-2.30(m, 3H); 308;2.39(s, 3H); 2.23-2.11(m, 3H); 1.80(s, 3H); 1.31(d, 12H). 232. 76COO-i-Bu Me H — 230-235 408 CDCl3: 8.53(s br, 1H); 7.18(m, 1H); 7.09(m,3H); 4.55(s (M+); br, 1H); 3.99(d, 2H); 3.26(d, 1H); 3.19(d, 1H); 3.06-182 2.91(m, 3H); 2.41(s, 3H); 2.40(m, 3H); 2.23-2.10(m, 2H); 2.08(s,3H); 2.05-1.91(m, 1H); 1.79(m, 1H); 0.97(d, 6H). 77 CON(i-Pr)₂ Me H−174.5 190-193 461 CDCl3(base): 8.05(s br, 1H); 7.20(m, 1H); 7.05(m,3H); (M+); 5.86(ddt, 1H); 5.21(d, 1H); 5.15(d, 1H); 4.57(s br, 1H); 361;3.93-3.83(m, 2H); 3.25-3.10(m, 4H); 3.08-2.89(m, 3H); 334. 2.51(m, 1H);2.41(d, 1H); 2.32(d, 1H); 2.21-2.09(m, 3H); 1.82(s, 3H); 1.30(d, 12H).78 CON(i-Pr)₂ Me H −308.3 206-216 519 CDCl3(base): 8.30(s br, 1H);6.64(d, 1H); 6.58(d, 1H); dec. (M+); 5.83(ddt, 1H); 5.42(s, 1H); 5.21(d,1H); 5.18(d, 1H); 419; 4.80(s br, 1H); 4.10-3.95(m, 2H); 3.90-3.80(m,2H); 392; 3.18-3.08(m, 4H); 2.75(dd, 1H); 2.62-2.51(m, 1H); 377; 2.45(d,1H); 2.32-2.20(m, 3H); 1.90(s, 3H); 1.78- 351. 1.68(m, 1H); 1.31(d, 6H);1.30(t, 3H); 1.29(d, 6H). 79 CON(i-Pr)₂ Me H −377.5 248-250 521 DMSO:6.8-6.6(m, 2H); 5.6(s, 1H); 4.65(q, 2H); 4.1- dec. (M+) 3.6(m, 6H);3.4-2.8(m, 4H); 2.5-1.7(m, 10H); 1.3 (m, 12H) 80

Me H −346.1 204-207 dec. 569 (M+) 525, 134, 91. DMSO(base, 373K):7.25(m, 5H); 6.6(m, 2H); 5.55 (s, 1H); 4.8-4.4(m, 4H); 3.7(s, 3H);3.4(m, 1H); 3.1 (d, 1H); 2.8-2.3(m, 9H); 2.1(m, 1H); 1.7-1.9(m, 5H);1.1(m, 6H). 81 COO-i-Bu Me H −415.2 196-200 493 CDCl3(base): 8.8(bs,1H); 6.6(q, 2H); 5.75-5.9(m, (M+) 1H); 5.4(s, 1H); 5.3-5.1(m, 2H);4.7(bs, 1H); 4.0(m, 4H); 3.2-3.0(m, 4H0; 2.8-2.65(dd, 1H); 2.6-2.45(m,2H); 2.35-1.9(m, 7H); 1.75(m, 1H); 1.3(m, 3H); 1.0 (m, 6H) 82 COOMe Me H−490.1 140 dec. 409.1 CDCl3(base): 6.6(q, 2H); 5.5(s, 1H); 3.95(s, 3H);(M+) 3.8(s, 6H); 3.25-2.85(m, 4H); 2.6-2.2(m, 8H); 2.1(s, 3H). 83CON(i-Pr)₂ Me H −455.4 187-190 492.2 (M+) 84 CON(i-Pr)₂ Me H −198.9178-182 536.1 (M+) 85 COO-i-Bu Me H −424.5 174-175 523.3 CDCl3(base):6.62-6.65(m, 2H); 5.10-5.42(m, 3H); dec. (M+) 4.20-4.35(m, 2H);3.9-4.0(m, 2H); 3.75(s, 3H); 3.22 (m, 1H); 3.05(d, 1H); 2.6-2.2(m, 8H);2.15(s, 3H); 2.0-1.7(m, 8H). 86 COO-i-Bu Me H −395.3 245-246 583.9CDCl3(base): 7.3-7.1(m, 5H); 6.7-6.55(m, 2H); 6.1 dec. (M+) (bs, 1H);5.55(s, 1H); 5.1(s, 2H); 4.6(m, 1H); 4.3- 4.15(m, 1H); 4.0-3.9(m, 2H);3.8(s, 3H); 3.25(m, 1H); 3.1(d, 1H); 2.6-2.2(m, 8H); 2.1(s, 3H);2.0-1.7(m, 4H); 0.9(d, 6H) 87 CON(i-Pr)₂ Me H −406.3 124-126 549.9CDCl3(base): 6.6(m, 2H); 5.4(s, 1H); 5.0(d, 1H); dec. (M+) 4.8-4.7(m,1H); 4.2(m, 2H); 3.8(s, 3H); 3.2(m, 1H); 3.0(d, 1H); 2.6-2.2(m, 8H);2.0-1.7(m, 9H); 1.5-1.1 (m, 15H). 88 CO-i-Bu Me H −660 138-140 434.9CDCl3(base): 6.6(m, 2H); 5.5(s, 1H); 3.95(s, 3H); dec. (M+) 3.85(s, 3H);3.25(m, 1H); 3.1(d, 1H); 2.6-2.2(m, H); 2.15(s, 3H); 2.15-1.75(m, 3H);0.95(m, 6H). 89 PO(OEt)₂ Me H −359.5 131-134 CDCl3(base): 8.6(bs, 1H);6.6(q, 2H); 5.4(s, 1H); dec. 4.2-3.0(m, 4H); 3.8(s, 3H); 3.25-3.0(m,2H); 2.6-2.2 (m, 5H); 2.4(s, 3H); 2.0(s, 3H); 1.95-1.75(m, 3H);1.3(m,6H). 90

Me H −338.2 >260 dec. 503.8 (M+) CDCl3(base): 8.56(bs, 1H); 6.65(m, 2H);5.4(s, 1H); 4.4-3.8(m, 3H); 3.8(s, 3H); 3.2(m, 1H); 3.1(d, 1H);2.6-2.3(m, 8H); 2.0-1.75(m, 6H); 1.2(m, 6H); 91 COO-i-Bu Me H−507.6 >250 dec. 423.1 CDCl3(base): 8.9(bs, 1H); 6.6(m, 2H); 5.4(s, 1H);(M+) 4.0(m, 2H); 3.8(s, 3H); 3.5(m, 1H); 3.1(dd, 1H); 2.8 (m, 3H);2.4(m, 2H); 2.15(s, 3H); 2.0-1.7(m, 4H); 1.0(d, 6H). 92 COO-i-Bu Me H−457.44 −250 dec. 422.8 CDCl3(base): 9.1(bs, 1H); 6.6-6.5(dd, 2H);5.4(s, (M+) 1H); 4.0(m, 2H); 3.2(m, 1H); 3.0(d, 1H); 2.6-2.3(m, 5H);2.4(s, 3H); 2.1(s, 3H); 2.0-1.7(m, 5H); 1.0(d, 6H) 93 COO-i-Bu Me H432.9 >270 dec. 523.0 DMSO(base): 11.5(s, 1H); 6.5(s, 2H); 5.9-5.7(m,(M+) 1H); 5.3-5.1(m, 3H); 4.7-4.5(m, 1H); 4.1-3.9(m, 4H); 3.2-2.9(m,5H); 2.8-2.55(m, 1H); 2.4-1.9(m, 6H); 2.05(s, 3H); 1.5(d, 1H); 0.9(d,6H). 94 COO-i-Bu Me H −479.4 235-237 501.9 CDCl3(base): 6.6(m, 2H);5.75(m, 1H), 5.55(s, 1); dec. (M+) 5.1-4.9(m, 2H); 4.0(d, 2H); 3.8(s,3H); 3.25(m, 1H); 3.1-1.0(d, 1H); 2.8(d, 3H); 2.6-2.25(m, 5H); 2.45(s,3H); 2.15(s, 3H); 2.05-1.75(m, 4H); 0.95(d, 6H). 95 COO-i-Bu Me H −577.6240-242 522.0 CDCl3(base): 6.6(m, 2H); 5.7(d, 1H); 5.5(s, 1H); dec. (M+)4.95(d, 1H); 3.9(m, 2H); 3.8(s, 3H); 3.2(m, 2H); 3.15(s, 3H); 3.0(s,3H); 2.6-2.2(m, 5H); 2.4(s, 3H); 2.1(s, 3H); 2.1-1.8(m, 4H); 0.9(d, 6H).96

Me H −412.5 244-246 dec. 434.0 (M+) CDCl3(base): 8.7(bs, 1H); 6.6(m,2H); 5.4(s, 1H); 3.8(s, 3H); 3.5(m, 4H); 3.3-3.0(m, 2H); 2.6-2.2(m, 5H);2.4(s, 3H); 1.9(s, 3H); 1.9-1.7(m, 7H). 97

Me H −386.1 262 dec. 447.8 (M+) CDCl3(base): 8.7(bs, 1H); 6.6(m, 2H);5.4(s, 1H); 3,8(s, 3H); 3.5(m, 4H); 3.3-3.0(m, 2H); 2.6-2.2(m, 5H);2.4(s, 3H); 1.9(s, 3H); 1.9-1.7(m, 9H). 98

Me H −376.2 258-260 dec. 449.9 (M+) CDCl3(base): 8.7(bs, 1H); 6.6(m,2H); 5.4(s, 1H); 3.8(s, 3H); 3.7(s, 3H); 3.6-3.5(m, 5H); 3.25-3.0(m,2H); 2.4(s, 3H); 2.6-2.2(m, 5H); 1.9(s, 3H); 2.0-1.8 (m, 3H). 99

Me H −424.8 255‥258 dec. 462.9 (M+) CDCl3(base): 8.7(bs, 1H); 6.6(m,2H); 5.4(s, 1H); 3.8(s, 3H); 3.6(m, 4H); 3.2(m, 1H); 3.05(d, 1H);2.6-2.2(m, 15); 2.0-1.8(m, 6H). 100 

Me H −301.0 106-107 dec. CDCl3(base): 8.7(bs, 1H); 6.6(m, 2H); 5.4(s,1H); 3.8(s, 3H); 3.6(m, 6H); 3.2(m, 1H); 3.0(d, 1H); 2.6-2.2(m, 12H);2.0-1.7(m, 9H). 101 

Me H −303.1 249-253 583.9 (M+) CDCl3(base): 8.5(s, 1H); 7.9(d, 2H);7.3(m, 2H), 6.65(m, 2H); 5.45(s, 1H), 4.6(q, 2H); 4.5(m, 3H); 3.8(s,3H); 3.25(m, 1H); 3.1(d, 1H); 2.55-2.2(m, 8H); 2.05-1.8(m, 6H); 1.4(t,3H); 1.15(m, 6H). 102 

Me H −368.3 215-220 555.8 (M+) CDCl3: 11.2(s, 1H); 7.85(d, 2H); 7.3(m,2H); 6.6 (q, 2H); 5.4(s, 1H); 4.6(s, 2H); 4.25(m, 1H); 3.65 (s, 3H);3.3(m, 1H); 3.1(d, 1H); 2.5-1.6(m, 14H), 0.9(m, 6H). 103 

Me H −303.5 200-204 583.9 (M+) CDCl3(base): 8.5(bs, 1H); 7.9(m, 2H);7.5-7.3(m, 2H); 6.6(m, 2H); 5.4(s, 1H); 4.7-4.3(m, 5H); 3.8(s, 3H);3.3(m, 1H); 3.1(d, 1H); 2.6-2.2(m, 8H); 2.0- 1.7(m, 6H); 1.4(t, 3H);1.15(m, 6H) 104 

Me H −318.8 242-246 556 (M+) CDCl3(base): 11.3(s, 1H); 7.8-7.75(m, 2H);7.5-7.3 (m, 2H); 6.75-6.65(q, 2H); 5.5(s, 1H); 4.6(s, 2H); 4.3(m, 1H);3.9(m, 1H); 3.7(s, 3H); 3.5-2.7(m, 9H); 2.3(m, 2H); 2.0-1.8(m, 4H);1.65(m, 1H); 1.1 (m, 6H). 105  COOMe Me H −425.9 150 dec. 412CDCl3(base): 6.68(d, 1H); 6.63(d, 1H); 5.52(s, (MH+) 1H); 3.82(s, 3H);3.81(s, 3H); 3.25(dd, 1H); 3.08 (d, 1H); 2.61-2.42(m, 4H): 2.44(s, 3H);2.33(ddd, 1H); 2.31(s, 3H); 2.01(ddd, 1H); 1.93(ddd, 1H); 1.82(dd, 1H).

What is claimed is:
 1. A compound, or a solvate or salt thereof, offormula (I):

in which, R₁ is hydrogen, linear or branched C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₄₋₆ cycloalkylalkyl, each of the latter three groups beingoptionally substituted by a hydroxy group when C_(≧2), C₃₋₅ alkenyl,aryl, aralkyl or furan-2 or 3-yl alkyl or (CH₂)_(m)COR wherein m is 0 to5 and R represents linear or branched C₁₋₆ alkyl, hydroxy, C₁₋₅ alkoxy,OC₃₋₆ alkenyl or alkylaryl, NR₁₀R₁₁ where R₁₀ and R₁₁ may be the same ordifferent, and each is hydrogen, linear or branched C₁₋₆ alkyl, C₄₋₆cycloalkylalkyl, C₃₋₅ alkenyl, aryl or aralkyl; R₂ is hydrogen, hydroxyor C₁₋₅ alkoxy, halogen, nitro, NR_(10a)R₁₁, or SR_(10a), where R_(10a)is hydrogen, linear or branched C₁₋₆ alkyl, C₄₋₆ cycloalkylalkyl, C₃₋₅alkenyl, aryl, aralkyl or COR₁, and R₁₁ has the same meaning describedabove; R₃ is hydrogen, linear or branched C₁₋₆ alkyl, hydroxy, C₁₋₅alkoxy, halogen, or (CH₂)_(m)COR where m and R have the same meaningdescribed above, SR₁₀, nitro, NR₁₀R₁₁, NHCOR₁₀, NHSO₂R₁₀, where R₁₀ andR₁₁ have the same meaning described above; R₄ and R₅, which may be thesame or different, are each independently hydrogen, hydroxy, C₁₋₅alkoxy, O-phenyl or together may form an oxy group (—O—); or R₄ togetherwith R₃ may form a methylenedioxy group (—OCH₂[2]O—); R₆ is CONH₂,CONMe₂, CONEt₂, CON(i-Pr)₂, CON(i-Pr)CH₂Ph, CON(i-Pr)(CH₂)₂OH,CON(CH₂CF₃)(i-Pr), COOMe, COOEt, COO-n-Pr, COO-i-Pr, COO-i-Bu,COOCH(i-Pr)₂, CSNEt₂, CSN(i-Pr)₂, COOH, COMe, CO-i-Pr, CO-i-Bu, CO-t-Bu,CO-3-pentyl, COPh,

 or PO(OEt)₂; R₇ is hydrogen, C₁₋₁₈ alkyl, C₂₋₁₈ alkenyl, halogen,halogen-C₁₋₆ alkyl, (CH₂)_(m)COR where m and R have the same meaningsdefined above or is a group

 or a five- or six-membered heteroaromatic group, containing up to threeheteroatoms selected from O, S and N, and substituted with R₃ in whichR₃ has the same meaning described above; R₈ is hydrogen or C₁₋₆ alkyl; nis 0; X and Y are independently oxygen, sulphur, CH or a R₆- orR₇-substituted carbon atom, and NR₉, where R₉ is hydrogen, linear orbranched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkylalkyl, each of thelatter three groups being optionally substituted by a hydroxy group whenC_(≧2), or may contain a NR_(10b)R_(11b) group where R_(10b) and R_(11b)may be the same or different and each is hydrogen, linear or branchedC₁₋₆ alkyl, C₄₋₆ cycloalkylalkyl, C₃₋₅ alkenyl, aryl, aralkyl, C₃₋₅alkenyl, aryl, aralkyl or (CH₂)_(m)COR wherein m is 0 to 5 and Rrepresents hydroxy, C₁₋₅ alkoxy, OC₃₋₆ alkenyl or alkylaryl,NR_(10c)R_(11c) where R_(10c) and R_(11c) may be the same or different,are each hydrogen, linear or branched C₁₋₆ alkyl, C₄₋₆ orcycloalkylalkyl.
 2. A compound according to claim 1 in which R₁ ishydrogen, methyl, ethyl, propyl, i-propyl, allyl, benzyl, phenyl-ethyl,CH₂CH₂OH, CH₂COOH, CH₂COOEt, CH₂CONH₂ or COMe.
 3. A compound accordingto claim 1 in which R₃ is hydrogen, hydroxy, ethyl, bromine, hydroxy,methoxy, ethoxy, i-propoxy, COMe or OCH₂COOH.
 4. A compound according toclaim 1 in which R₄ and R₅ are each hydrogen, hydroxy, acetyloxy,methoxy, O-phenyl, or together form an oxy group, or R₄ together with R₃is a methylenedioxy group.
 5. A compound according to claim 1 in whichn=0, X is NH and Y is CH or a R₆- or R₇-substituted carbon atom, whereR₆ is CONH₂, CONMe₂, CONEt₂, CON(i-Pr)₂, CON(i-Pr)CH₂Ph,CON(i-Pr)(CH₂)₂OH, CON(CH₂CF₃)(i-Pr), COOMe, COOEt, COO-n-Pr, COO-i-Pr,COO-i-Bu, or COOCH(i-Pr)₂; and R₇ is methyl or halogen-C₁₋₂alkyl.
 6. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier.
 7. A process for thepreparation of a compound of formula (I) as defined in claim 1 or asolvate or salt thereof, which comprises condensing a compound offormula (a), where K is H, Br, COR₇, ═CHOH or ═NOH, with a compound offormula (b), where Q is COR₇, CHClR₇, COR₇, SH or NH₂, and J is ═NNHPh,═O, ═H₂, or ═CHR₇, where R₇ and R₆ are as defined in claim 1

and optionally thereafter converting the compound of formula (I) to asolvate or salt thereof.